Thank you for taking the time to review the applicant abstracts. Below are the scientific and lay summaries, they are broken up by applicant number which corresponds to the decision form here: https://forms.gle/m8q9NCxiQi3dGVg18
The preference ratings are as follows:
1. Conflict
2. Very Interested (we ask you to select at least 10. This is simply to provide the review chairs with flexibility. You will not be assigned that many.
3. Interested
4. No Preference
5. Not at all Interested (reserve this rating for those grants for which you feel you lack expertise)
Please review the abstracts and compete your selections by Thursday, November 30, 2023.
Applicant 1
Name: Kaat Durinck PhD
Institution: Ghent University
Project Title: Dissecting the dynamic interplay between the nuclear pore complex and the epigenetic modifier PHF6 in neuroblastoma
General Audience Summary: Neuroblastoma is a deadly cancer that occurs in young children. Although some of the patients can be cured with an intense therapy schedule, the chance for cure is very small if the disease does not respond to standard treatment or returns. We previously discovered that the cancer cells experience stress due to their rapid growth and also become further damaged. Neuroblastoma cells have a number of properties that enable them to cope with this stress and control this damage. In this project we aim to better characterize new factors that we identified to be involved in these processes and this project aims to maximize the chances of successful treatment based on our new findings.
Scientific/Technical Abstract: Current working models of gene regulatory processes underscore the importance of orchestrated activities of transcription factor complexes, chromatin dynamics or modifications and higher-order DNA looping. More recently, physical distribution and contact with the nuclear lamina and the array of nuclear pores have emerged as crucial spatial factors that take part in transcriptional networks. Rewiring of these constellations is key in malignant transformation and has therefore emerged in the past decade as a target of strong therapeutic value. The mechanistic and clinical impact of nuclear pore mediated processes in cellular dysfunction has only to limited extent been explored in adult cancers and remains unexplored in pediatric malignancies. Based on our preliminary data, we propose to perform a detailed dissection of the poorly characterized epigenetic modifier PHF6 as a putative novel and key chromatin adaptor shaping the (epi)genetic landscape in neuroblastoma in concertation with the nuclear pore. This interaction could play a significant role in emerging nuclear pore moonlighting functions i.e. orchestration of gene gating, replication fork dynamics and DNA damage repair. Second, we will address how PHF6 can serve as entry point for synthetic lethality in neuroblastoma.
Applicant 2
Name: Dr. Tomer Cooks
Institution: Ben-Gurion University of the Negev
Project Title: Organotropic deposition of extracellular vesicles shed by PDAC cells harboring mutant p53 can remodel and prime the metastatic niche
General Audience Summary: Pancreatic cancer is a highly aggressive and lethal disease, with limited treatment options. Understanding the mechanisms that drive the spread (metastasis) of this cancer to other organs is crucial for developing effective therapies. Our research aims to explore the role of tiny cell derived particles called extracellular vesicles (EVs) in this process. Specifically, we are investigating how mutant p53 (mutp53), a common genetic mutation in pancreatic cancer, influences these EVs and promotes the cancer's aggressive behavior. Our findings could open avenues for personalized treatments, early detection methods, and targeted therapies, ultimately improving the lives of patients affected by this devastating disease.
Scientific/Technical Abstract: This proposal aims to comprehensively investigate the intricate interplay between mutant p53 (mutp53) and extracellular vesicles (EVs) in driving metastasis of pancreatic ductal adenocarcinoma (PDAC). Aim 1 seeks to elucidate the biodistribution and tissue remodeling potential of mutp53-derived EVs. Using murine models, EVs will be fluorescently labeled and administered via various routes, with subsequent bio-distribution analysis. Tissue remodeling will be examined through CyTOF multiplex analysis and RNAseq, shedding light on mutp53 EV induced alterations in metastatic sites. Aim 2 focuses on investigating the role of ITGB4 (a key integrin found to play a major role in metastasis), packaged in EVs, in driving aggressive phenotypes of mutp53 PDAC. CRISPR-engineered ITGB4 knockout cells will be utilized to explore the impact of exosomal ITGB4 on pro-cancerous traits in vitro. Further, the study delves into the effect of ITGB4 EVs on mutp53 EV bio-distribution and their influence on tumorigenesis and metastasis. These aims, supported by robust experimental methodologies, will provide critical insights into the molecular mechanisms governing mutp53 EV-induced metastasis and the importance of the premetastatic niche primed by EVs. The findings promise to unravel novel therapeutic avenues for PDAC and potentially other cancers, emphasizing the pivotal role of mutp53-derived EVs in cancer progression.
Applicant 3
Name: Dr. Sheera Adar
Institution: The Hebrew University of Jerusalem
Project Title: RNA stabilization as a DNA damage response
General Audience Summary: Harmful agents in our environment, such as ultraviolet (UV) radiation in sunlight and cigarette smoke, increase cancer risk. Both these agents cause cancer primarily because they damage the DNA in cells. These damages in the DNA block the ability of the cells to function and lead to mutations. Every cell in our body harbours multiple pathways to cope with and repair DNA damages. We have recently uncovered a novel coping mechanism of cells, designed to allow them to continue to function while the DNA damages are being removed. Our goal is to underhand this damage-response mechanism in order to improve cancer risk assessment and cancer prevention.
Scientific/Technical Abstract: DNA damages are a major driving force for carcinogenesis and enhanced cancer risk. Especially deleterious are bulky, helix-distorting base-damages that block transcription and replication. These include damages induced by ultraviolet (UV) radiation in sunlight, and by components of cigarette smoke. The DNA damage response to these damages includes a global shutdown of transcription until damages are repaired. However, repair of some damages requires 24 hours or more. One coping mechanism could be to enhance the stability of existing RNAs when the synthesis of new RNA is compromised, but this has not been systematically examined. We measured RNA stability before and after UV treatment, and found that thousands of transcripts are stabilized in response to transcription-blocking damages. The stabilized transcripts include genes involved in RNA metabolism and modifications, and key DNA repair genes. In this project, we will study this newly discovered phenomenon of damage-induced RNA stabilization to decipher its underlying mechanism. Establishing RNA stabilization as a novel and critical component, of the global DNA damage response will lead to a better understanding of the process of carcinogenesis and could lead to new strategies for cancer risk assessment and therapy.
Applicant 4
Name: Dr. Lucia Borriello
Institution: Temple University - Of The Commonwealth System of Higher Education
Project Title: Role of Chemotherapy in Promoting Awakening of Dormant Tumor Cells and Metastatic Relapse
General Audience Summary: Neoadjuvant chemotherapy (NAC) is the standard of care for triple-negative breast cancer (TNBC). Although many patients respond well, many develop lung metastasis relatively soon after NAC. Metastases arise from tumor cells that escaped from the primary tumor and seeded distant organs, such as lungs, where they survive in a dormant state. When dormant cells are triggered to awaken, they proliferate and form metastases. Paradoxically, awakening may be triggered by NAC. Our project seeks to understand how NAC awakens dormant tumor cells to promote metastases. Longer-term, this work will help develop strategies to prevent this significant drawback of NAC, and thus enhance NAC efficacy.
Scientific/Technical Abstract: Mortality from triple-negative breast cancer (TNBC) is due to metastasis. Metastases arise from the awakening of dormant disseminated tumor cells (DTCs), which seed distant organs. Neoadjuvant chemotherapy (NAC) is the standard of care for TNBC. While NAC is effective for many TNBC patients, 25% develop lung metastases within 6 months of treatment. Evidence suggests that stresses induced by NAC might paradoxically promote the awakening of dormant DTCs. However, very little is known about how NAC awakens dormant DTCs. Our preliminary data demonstrated that paclitaxel promotes the awakening of dormant tumor cells in the lung, leading to metastases. Further, paclitaxel induces lung fibroblasts to secrete CXCL1, a proinflammatory cytokine. Therefore, we hypothesize that NAC promotes metastasis by stressing lung fibroblasts, which in turn secrete CXCL1, which triggers the awakening of dormant DTCs in the lung. We propose two aims: AIM 1. Determine the role of CXCL1 secreted by NAC-treated lung fibroblasts in promoting the awakening of dormant DTCs. AIM 2. Identify the mechanism by which NAC-treated lung fibroblasts trigger the awakening of dormant DTCs. This study will identify new mechanisms for strategies to reverse the NAC-induced awakening and improve NAC efficacy.
Applicant 5
Name: Dr. Yang Chen
Institution: The University of Texas MD Anderson Cancer Center
Project Title: Targeting collagen I homotrimer induced IL-18 as a novel therapeutic strategy in pancreatic cancer
General Audience Summary: Pancreatic cancer has a dismal survival rate and is refractory to most therapies. The drugresistant feature of pancreatic cancer is associated with its desmoplastic ‘scar-like’ stroma highly enriched in collagen-I. However, the functions of collagen-I remain controversial. My paradigm-shifting discoveries identified that pancreatic cancer cells uniquely produce the abnormal ‘bad’ collagen-Ihomotrimer, in contrast to the normal ‘good’ collagen-I-heterotrimer produced by fibroblasts. Collagen-Ihomotrimer drives pancreatic cancer progression and immunosuppression by upregulating a key factor Interleukin-18 (IL-18). Targeting Interleukin-18 may provide new opportunities for blocking type I collagen homotrimer-induced oncogenic effect and enhancing the efficacy of immunotherapy.
Scientific/Technical Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths. PDAC has a dismal survival rate and is refractory to most therapies. There are urgent needs to identify new therapeutic strategies for PDAC. A hallmark feature of PDAC is its desmoplastic ‘scar-like’ stroma. However, generic targeting strategies of PDAC stroma have mostly failed in the clinic or, in some cases, even accelerated tumor progression. PDAC stroma is highly enriched in type I collagen (Col1). However, the contribution of Col1 to PDAC remains controversial. Our paradigm-shifting studies discovered the two distinct subtypes of Col1: homotrimer and heterotrimer, with opposing biological effects. Delineating the differences between Col1 homotrimer and Col1-heterotrimer is critical for developing strategies to specifically target oncogenic Col1-homotrimer without disturbing normal Col1-heterotrimer. To address this, we identified Interleukin-18 (IL-18) as a novel downstream factor of Col1-homotrimer pathway with oncogenic and immunosuppressive functions, representing a novel therapeutic target. Interleukin-18 expression is highly enriched in PDAC and correlates with poor prognosis in PDAC patients. We generated a novel transgenic mouse model with Interleukin-18 knockout in PDAC to investigate the key role of Interleukin-18 in tumor progression and immunosuppression. Targeting Interleukin-18 may suppress PDAC progression, reverse the immunosuppression, and enhance immunotherapy.
Applicant 6
Name: Dr. Akihiro Yoshida
Institution: Case Western Reserve University
Project Title: Enhancing immunotherapy efficacy by novel senolytic approach for targeting therapy-resistant Braf mutant cutaneous melanoma
General Audience Summary: Cells in our body have a protective feature that stops them from growing when they're stressed or damaged. However, some cells can still create a harmful environment around them, possibly leading to diseases like cancer. Scientists are exploring a new treatment to remove these problematic cells. In our studies, we found a combination of two drugs that can act as a cleanup crew, targeting melanoma. Current treatments work for only about 30-40% of patients. Our approach could offer a new option for those who haven't found success with standard treatments and might even improve the efficacy of existing immunotherapy approaches.
Scientific/Technical Abstract: Senescence plays a crucial role in preventing the proliferation of damaged or dysfunctional cells. In recent years, senescence has emerged as a double-edged sword mechanism for cancer. While the loss of proliferative capacity of senescent cells prevents the accumulation of aberrant cells, senescent cells form chronic microinflammation in the surrounding microenvironment, promoting carcinogenesis. Senolytic therapy is an emerging therapeutic approach that specifically eliminates senescent cells. Incorporating senolytic therapy into existing cancer treatment regimens has the potential to significantly improve patient outcomes. We demonstrated that the combination of CDK4/6 inhibitor and GLS1 inhibitor is a novel senolytic therapy targeting Braf mutant melanoma even though with Braf inhibitor-resistant melanoma cells. This suggests a potential clinical application for treating Braf mutant melanoma as a second-line therapy. Although immunotherapies are the first-line treatment for advanced melanoma, response rates for checkpoint immunotherapy are 30 to 40% in patients, underscoring a critical need for therapeutic improvement. In this proposal, we will determine whether the proposed novel senolytic therapy alters the tumor microenvironment and improves current immunotherapy efficacy using mouse models. This proposal has the potential to address the clinical challenges of therapy-resistant melanoma.
Applicant 7
Name: Dr. Yoav Shaul
Institution: Hebrew University
Project Title: Nucleotide Biosynthesis as a Regulator of EMT in Cancer
General Audience Summary: The journey of cancer cells towards metastasis involves a transformation that boosts their ability to migrate. This transformation, called the epithelial-mesenchymal transition (EMT), results in cancer cells growing slower. Our research explores how EMT influences the production of specific cell metabolites called nucleotides and whether this contributes to the slowdown in growth. By uncovering these hidden connections, we aim to find new ways to stop cancers from turning into aggressive forms. Our study dives into the world of cancer biology and metabolism, aiming to shed light on this process and potentially open doors to more effective treatments.
Scientific/Technical Abstract: The initiation of the metastatic cascade is accompanied by alteration in the cells' characteristics as they gain mesenchymal-like properties, such as enhanced migratory capabilities. These cellular changes are induced by the epithelial-mesenchymal transition (EMT) program, which transdifferentiates the carcinomas into a partially mesenchymal state. Interestingly, one of the outcomes of this program is a decrease in the proliferation rate by yet unknown mechanisms. Here, we hypothesize that the EMT program decreases its proliferation rate by attenuating purine and pyrimidine biosynthesis. Our integrated model proposes that the EMT program reduces nucleotide biosynthesis flux, decreasing the abundance of building blocks and attenuating the proliferation rate. Therefore, we propose to systematically characterize any EMT-dependent changes in nucleotide biosynthesis. Furthermore, we will assess the effects of manipulating nucleotide levels on cell proliferation. Finally, we will explore the functional relevance of nucleotide fluctuations in promoting EMT associated cell plasticity. Our study is expected to uncover a novel principle in cancer biology by demonstrating the instructive role of metabolic processes in tumor progression. Understanding metabolic pathways in cancer cell dynamics holds promise for developing new therapeutic strategies aiming to prevent the de-differentiation of cancers to high-grade malignancies.
Applicant 8
Name: Dr. Anthony Nguyen
Institution: Cedars-Sinai Medical Center
Project Title: Targeting Innate Immune Checkpoints for Advanced Triple Negative Breast Cancer
General Audience Summary: Although immunotherapy is an emerging option for triple negative breast cancer, it is unclear how to best treat patients who are resistant to immunotherapy or patients who ultimately progress on therapy. Our preliminary preclinical and clinical data have identified a novel approach of using radiotherapy to reset the immune response and innate immune checkpoint targeting to stimulate or reactivate responses to immunotherapy in patients with triple negative breast cancer. We will characterize these previously unappreciated innate immune vulnerabilities using mouse models of breast cancer and cultured immune cells to identify new targeted treatments for immunotherapy-refractory breast cancer.
Scientific/Technical Abstract: Although immunotherapy is an emerging treatment option in triple negative breast cancer (TNBC), it is unclear how to best treat patients with immunotherapy-refractory disease. Using single-cell RNA sequencing, we found that several innate immune checkpoints including SIRPa CD47 are upregulated by tumor-associated macrophages (TAMs) from EO771 TNBC tumors treated with ablative radiotherapy. Targeting the SIRPa-CD47 checkpoint following anti-PD-1/RT was shown to metabolically reprogram TAMs, deplete myeloid-derived suppressor cells (PMN MDSCs), and enhance the antitumor efficacy of anti-PD-1/RT. We hypothesize that targeting innate immune checkpoints can enhance response to immunotherapy by favorably altering downstream signaling from the phagolysosome, which limits the recruitment of PMN-MDSCs. In Aim 1, we will characterize the in vivo trafficking of PMN-MDSCs to the immune microenvironment of the EO771 model and other non-TNBC models. In Aim 2, we will characterize the effect of SIRPa-CD47 blockade on phagolysosome content and downstream signaling using spatial resolved mass spectrometry. Successful execution of these aims will identify novel therapeutic targets beyond PD-1/PD-L1 in immunotherapy-refractory breast cancer, which currently has no curative intent treatment options.
Applicant 9
Name: Dr. Cameron Bracken
Institution: University of South Australia
Project Title: A new class of RNA for anti-cancer therapy
General Audience Summary: RNA therapy presents a promising strategy to target genes that drive cancer. Here, we develop a novel RNA therapy strategy that targets entire groups of cancer-promoting genes, striking a balance between achieving anti-cancer effects whilst minimizing potential side effects. To do this, we will optimize our therapeutic RNAs and utilize them to halt the progression of liver cancer. This new approach offers an exciting opportunity to combat cancer with improved efficacy and fewer adverse effects.
Scientific/Technical Abstract: RNA therapeutics offer tremendous potential in cancer therapy as they can suppress genes encoding proteins that are “undruggable” by classical small molecules, using a technology that is quick in both drug design and synthesis. Drug specificity and toxicity however remain concerns. To address this, we have developed a novel type of RNA (a “miRNA/siRNA hybrid”) that we design to cross-target genes within oncogenic signaling pathways, and that are optimized to reduce “off-target” effects on other genes. These hybrid RNAs are then further combined, providing co-operative targeting at very low concentrations to increase safety and efficacy. We have extensive preliminary data that these co-operative small RNAs are effective at suppressing the oncogenic RAS pathway in multiple liver, breast and melanoma cell lines and specifically decrease the viability of RAS-dependent (but not RAS independent) cancer cells. This project will test the capacity of RNA hybrids to treat liver cancer in vivo (a tissue for which the targeted delivery of RNA is possible). An online freely available tool will also be developed to accelerate the design of further anti-oncogenic RNAs by other researchers.
Applicant 10
Name: Dr. Yejing Ge
Institution: UT MD Anderson Cancer Center
Project Title: Elucidating the molecular and cellular pathogenesis of endogenous retroviruses in skin cancer
General Audience Summary: Almost half of our genome is constituted of retrotransposons. Many retrotransposons have invaded our genome as ancestral retroviruses and become interspersed genomic repeats that largely degenerate or are coopted for host functions. Retrotransposons are reactivated in many human cancers, though the extent to which they ensue viral form and function is unclear, and molecular trigger remains poorly defined. This work uses skin as a model to study the molecular pathogenesis of viral-coding retrotransposons, known as the endogenous retroviruses. By leveraging these basic mechanisms, we exploit innovative treatment strategies for squamous cancer patients.
Scientific/Technical Abstract: Transposons are interspersed genomic repeats that constitute 40% of the mammalian genome. Most retrotransposons are either degenerated or domesticated as host regulome to orchestrate lineage gene expressions, while an extraordinary group morphed into host proteins or donated coding functions during a critical stage of mammalian development. A few rare evolutionarily young species remain virally active, causing germline mutations and modulating immune functions. Retrotransposon activities are widely observed in cancers, though the extent to which retrotransposons exert active viral form and function is unclear. Their molecular trigger in adult pathology is poorly defined. Here, we propose to address these challenges by using a genetic model lacking what we have found to be a crucial epigenetic repressor of retrotransposons in adult skin. Built on genetic and functional genomic tools we have developed in the lab, we exploit our ability to read and perturb retrotransposons in the skin. Our preliminary data revealed potent and selective reactivation of endogenous retroviruses (a type of retrotransposons) in our model, through which we will systematically dissect host mechanisms restraining endogenous retroviruses and how to leverage their reactivations to treat squamous cancers.
Applicant 11
Name: Dr. Francesco Baschieri
Institution: Medical University Innsbruck
Project Title: Energy-Efficient Adhesions in Cancer Cell Migration and Metastasis
General Audience Summary: Metastases stem from cancer cells that excel at colonizing distant organs due to their adaptive capabilities. For cancer cells to migrate to distant organs, they must establish connections with their surroundings. This is facilitated by structures known as focal adhesions. Migrating cells spend up to 50% of their total cell energy to form and maintain focal adhesions. Yet, metastatic cancer cells migrating in three-dimensional spaces (as in our body) can rely on alternative adhesive structures that require less energy. Like efficient cars, cells employing energy-saving adhesions can cover greater distances, which translates into more aggressive disease progression. By studying the adhesive plasticity of disseminating cells, we aim at identifying new targets to fight metastases.
Scientific/Technical Abstract: Metastatic cancer cells are characterized by a high plasticity that allows them to thrive in the most disparate environments. To evade anoikis, cells need to establish and maintain contacts with their surroundings. Focal adhesions (FAs) are the primary sites of cellular adhesion and form in response to tension on the actin cytoskeleton. The energy-intensive process of remodeling the actin cytoskeleton makes Focal adhesions (FAs) inherently costly structures. Here, we propose to study endocytosis-related adhesions (ERAs), an alternative adhesive feature that auto-assemble in response to curvature without the need of energy. Disseminating cancer cells moving in the interstitial spaces of our body are confronted with collagen fibers that induce curvatures, and hence adhesions, on their membranes. To generate curvature and induce ERAs, we will employ nanolithography and fabrication of collagen fibers. We will start by measuring how much energy is effectively spared by using ERAs over FAs. Then, using both hypothesis-driven and –omics approaches, we will investigate the molecular mechanisms governing the transition between adhesion types in response to energy reduction. Finally, we will employ an ex-vivo system to study invasion across decellularized mouse organs. Overall, our project aims at characterizing a new form of plasticity involved in metastatic dissemination of cancer with the objective of identifying potential new targets for anti-metastatic therapies.
Applicant 12
Name: Dr. Tianshun Zhang
Institution: Regents of the University of Minnesota
Project Title: Role of CD70 in solar UV-induced skin damage, immune response, and photocarcinogenesis
General Audience Summary: CD70, an emerging immune checkpoint, is gaining attention in various cancers. This project focuses on understanding its role in nonmelanoma skin cancer (NMSC), which often results from UV radiation exposure. We aim to explore how CD70 affects immune responses, skin damage, and cancer development. Specifically, we'll investigate how CD70, and its receptor interacts with immune cells and skin cells (keratinocytes) in the context of UV-induced skin cancer. By uncovering the role of CD70, we aim to improve our knowledge of skin cancer development and find new ways to prevent and treat NMSC.
Scientific/Technical Abstract: CD70, a novel immune checkpoint, garners attention for its relevance in various cancers. Our study focuses on CD70's role in nonmelanoma skin cancer (NMSC), primarily caused by UV radiation. Immune checkpoints play a crucial role in balancing immune responses and self-tolerance. CD70 and its receptor, CD27, exhibit abnormal expression in different cancers, particularly solid tumors. However, their significance in NMSC, driven by UV radiation, remains unclear. Our research aims to explore CD70's impact on immunomodulation, skin damage, photocarcinogenesis, and its role in communication between keratinocytes/SCC cells and immune cells via CD27 interaction. We hypothesize that CD70 uniquely regulates solar UV-induced skin damage and photocarcinogenesis by influencing various signaling pathways. Notably, the CD70/CD27 interaction plays a pivotal role in shaping immune responses during skin damage and carcinogenesis. This study is a significant step toward unraveling NMSC mysteries and potential therapeutic applications.
Applicant 13
Name: Dr. Bettina Nadorp
Institution: NYU Grossman School of Medicine
Project Title: Epigenetic and Transcriptomic Immune Determinants of Poor Outcome Acute Myeloid Leukemia
General Audience Summary: Patients with acute myeloid leukemia who have co-mutations in NPM1 and WT1 genes are at high risk of death. However, they are classified as 'favorable risk' in current clinical practice, which prevents the use of more aggressive treatments. The bone marrow niche provides support to the leukemic cells and is involved in therapy resistance leading to poor outcomes. We will use singlecell technologies and mutation profiling to study the cellular interactions between leukemia and the bone marrow niche. These studies will lead to a better understanding of the disease and new therapeutic treatment options that will improve outcomes.
Scientific/Technical Abstract: Despite compelling data demonstrating the poor prognostic effect of WT1-NPM1 co-mutated AML, current guidelines do not incorporate WT1 mutations, resulting in favorable-risk classification in the absence of other poor prognostic lesions. The mechanisms underlying the particularly high-risk disease biology are unknown. The bone marrow (BM) immune microenvironment has been implicated in therapy resistance, disease progression, and inferior survival in AML. We hypothesize that the dysregulated immune microenvironment contributes to low survival. Here, we propose a detailed epigenetic and transcriptomic single-cell dissection of the BM immune microenvironment, including mutational profiling on the single-cell level in WT1-NPM1 co-mutated AML. The results of these studies will provide a fundamental understanding of the role of WT1 co-mutations in the pathogenesis of NPM1-mutated AML and lead to the discovery of novel treatment strategies that will improve outcomes.
Applicant 14
Name: Dr. Tanner Johanns
Institution: Washington University in St. Louis
Project Title: TERT as a therapeutic target for CAR T cell therapy in glioblastoma
General Audience Summary: The failure of immunotherapy in patients with glioblastoma (GBM) has been discouraging, but the diversity and potency of the host immune system still offers hope. One promising approach in GBM is chimeric antigen receptors (CAR) that redirect host immune cells to specifically recognize tumor antigens. A major limitation of this approach is antigen selection, whereby antigens are either heterogeneously expressed on tumor cells and/or can be easily downregulated leading to immune escape and resistance to CAR-based therapies. We aim to show that CARs against the tumor-associated antigen, hTERT, overcomes these mechanisms of resistance and represents an ideal target in GBM. This proposal aims to validate hTERT as a viable target for CAR therapy that can be translated into the clinic.
Scientific/Technical Abstract: Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults. Chimeric antigen receptor (CAR) based immunotherapies have demonstrated some efficacy in GBM but results have been hindered by immune escape driven by heterogenous target antigen expression. A more ideal target would be diffusely expressed in all patients and on all tumor cells, as well as a driver of cancer biology. Activating mutations in the promoter of human TERT (hTERT) meets these criteria as: they are found in >90% of GBM patients; are clonal mutations present in all tumor cells; and are drivers of malignant transformation. T cell receptor (TCR)-like antibodies can recognize peptides derived from intracellular proteins like hTERT that are processed and presented on the surface of tumor cells in the context of HLA molecules. We have recently identified 3 hTERT-derived peptides – p331, p865, and p934, complexed to HLAA* 02:01 (HLA-A2). hTERT p865 has previously been identified as an immunodominant HLA-A2-restricted antigen in vaccine studies, while hTERT p331 and p934 have not been characterized. In this proposal, we will test the hypothesis that hTERT p865:HLA-A2 CAR T cells are able to selectively recognize and kill GBM cells expressing the cognate antigen and improve outcomes for tumor-bearing mice. We will also test the hypothesis that TCR-like antibodies can be generated against the novel hTERT p331 and p934 peptide:HLA-A2 complexes to increase the valency of therapeutically relevant hTERT specific CAR constructs.
Applicant 15
Name: Dr. Jessalyn Ubellacker
Institution: Harvard T.H. Chan School of Public Health
Project Title: Discovery of lymph node biomarkers to target and prevent breast cancer metastasis
General Audience Summary: The major reason breast cancer causes illness and death in patients is because breast cancer cells can travel to lymph nodes or into the blood to then spread to other organs in the body, such as the lung or liver. However, the harsh environment of the blood kills most breast cancer cells before they make it to other organs. We previously discovered cancer cells that travel to the lymph nodes acquire changes to lipids, specifically oleic acid, inside of the cell that shield them from cellular stress and allows the cancer cells to survive. We anticipate we can use new drugs to induce cellular stress in breast cancer cells in lymph nodes to kill the cancer cells. The goal of our proposal is to use novel tools and drugs to induce cellular stress in breast cancer cells in the lymph nodes to halt cancer spread.
Scientific/Technical Abstract: Although most breast cancer deaths are caused by distant metastasis, the mechanisms that regulate metastasis are poorly understood. Regional lymph node metastasis in breast cancer is associated with worse prognosis. During metastasis, cancer cells encounter oxidative stress in the blood, and we recently discovered cancer cells in lymph are protected against ferroptosis – a process that causes cell death by lipid oxidation (Ubellacker et al., Nature 2020). Our findings suggest it may be possible to target metabolism in cancer cells to prevent cancer spread in lymph nodes. The objective in this proposal is to identify lipid and metabolic changes in breast cancer cells in lymph nodes that confer protection from lipid oxidation and may be used as biomarkers for predicting worsened disease prognosis. We hypothesize that certain breast cancer cells in lymph nodes have targetable metabolic traits that allow them to withstand lipid oxidation and metastasize to distant organs. In this proposal, we will use both existing and novel drugs to prevent these identified metabolic changes to block metastasis. To achieve this, we will use patient lymph node biopsy samples and relevant mouse breast cancer models of metastasis. This work is significant because we will be able to identify new therapeutic targets to prevent the spread of early stage breast cancer and ultimately improve disease outcome in patients.
Applicant 16
Name: Dr. Lai Chan
Institution: Cleveland Clinic Foundation
Project Title: RAS-NOTCH1 pathway interference subverts leukemogenesis
General Audience Summary: B-cell acute lymphoblastic leukemia (B-ALL) is a common childhood cancer that happens when white blood cells grow out of control. Currently, we use treatments that inhibit the main pathway causing the cancer, but leukemia often stops responding to these treatments and come back. When that happens, more than half of children and adults with leukemia do not survive. To tackle this problem, we propose a new treatment approach. Instead of directly inhibiting the main pathway, we will activate other pathways that inhibit the main pathway to stop leukemia growth. If our approach works, it could lead to faster and better treatments for leukemia, and maybe for other cancer types in the future.
Scientific/Technical Abstract: This proposal presents a novel approach to treat B-cell acute lymphoblastic leukemia (B-ALL) by activating inhibitory signaling pathways against the principal oncogenic driver, thereby hindering leukemia growth (termed “pathway interference”). Despite recent treatment advances, survival rates for relapsed B-ALL in children and adults remain below 50%. Therefore, developing treatments targeting specific vulnerabilities of B-ALL to lower relapse rates is crucial. About 35% of B-ALL cases carry mutations activating the RAS-RAF-MEK-ERK pathway. We hypothesize that NOTCH1, instead of promoting leukemia, inhibits ERK activity, disrupting RAS driven leukemia development. We here propose two aims: Aim 1 will determine if NOTCH1 activity antagonizes RASdriven leukemogenesis. We will test whether activating both pathways simultaneously halts leukemia and whether inhibiting NOTCH1 promotes RAS-driven leukemia initiation. Aim 2 will determine if pathway interference between RAS and NOTCH1 can be exploited for therapeutic benefit in B-ALL. For proof-of-concept, we will investigate the effects of activating the NOTCH1 pathway using agonistic Delta-like and Jagged ligands in RAS-pathway mutated B-ALL. If successful, our approach will establish a new framework for developing cancer therapies.
Applicant 17
Name: Dr. Yuxuan Miao
Institution: The University of Chicago
Project Title: Decipher the stem cell-intrinsic immune resistance
General Audience Summary: Head and neck cancers are among the most common and deadly cancers worldwide. Immunotherapy, which uses the body's immune system to fight head and neck cancer, has shown promise in the treatment. However, many patients’ tumor will grow back after the treatment. The objective of this proposal is to determine the critical factors that can help a group of special tumor cells known as tumor initiating cells to survive immunotherapy treatment in head and neck cancers. We will then test whether blocking any of these identified targets can dramatically enhance the efficacy of current immunotherapies and prevent relapse, providing insights for developing more effective immunotherapy.
Scientific/Technical Abstract: The treatments for head and neck squamous cell carcinomas and many other cancers have been revolutionized by the development of immunotherapies. However, more than 60% of immunotherapy treated cancer patients often experience relapse, the nature of which is still poorly understood. For advancing clinical outcomes of future treatments, the goal of this proposal is to identify key targets driving cancer relapse from immunotherapy. Recently, we discovered a group of TGFβ-responding tumor-initiating cells, which appears to be the major survivor of immunotherapy treatment and the cause of tumor relapse. This key finding raised the possibility of targeting the critical molecular programs driving the unique immune resistance of these special cancer cells to prevent cancer relapse. In this study we will develop an integrative immune-oncology platform to achieve rapid and specific genetic manipulation of tumor initiating cells directly in spontaneous tumors on live mice. With this powerful approach we aim to identify the stem cells-specific transcriptional network that governs the tumor initiating cell intrinsic immune resistance. This study will pave the way for developing new immunotherapy with the capacity to overcome relapse.
Applicant 18
Name: Dr. Beatrice Rondinelli
Institution: Gustave Roussy Hospital/CNRS
Project Title: How chromatin dysfunction drives defective repair in BRCA mutant cancers
General Audience Summary: Chromatin, the cell’s nuclear structure that wraps our DNA, protects it from damage and mutations, which is crucial for cell survival. Based on our data, we identified a new chromatin factor that we hypothesize may hold uninvestigated functions in this process, that will be investigated in this project. We will test whether the factor plays its protective role on the genome by interacting with or by chemically modifying unidentified proteins. Our study may uncover new mechanisms through which a specific type of breast cancer accumulates mutations. Ultimately, our research may provide foundation to explain the bad prognosis of this cancer and provide knowledge to improve their response to therapy.
Scientific/Technical Abstract: Chromatin, formed by DNA wrapped around histone proteins, contributes to DNA damage repair to maintain genome integrity, but several pathways remain uncharacterized. Through bioinformatics, we identified that the methyltransferase KMT2D is present at DNA damage sites and its levels regulate the sensitivity to DNA damage. We show that KMT2D loss induces aberrant DNA damage and genome instability in human cells. Moreover, its lossof-function specifically impacts the survival of BRCA1/2 mutant breast cancers and cell lines, pointing at uninvestigated tumor suppressive functions of KMT2D in the DDR that are crucial for genome integrity. This led us to hypothesize that KMT2D may exert its DDR function by interacting with or methylating unidentified downstream DDR effectors. We will identify new, nonhistone interactors (Aim 1) and methyl targets (Aim 2) of KMT2D. Next, through functional DNA repair and genome instability assays, we will investigate whether the identified effectors contribute to the DDR/genome integrity functions of KMT2D (Aim 3). Ultimate objective of this project is to dissect KMT2D-dependent pathways of DDR that, when disrupted, may impinge the genome integrity and survival of cancer cells, specifically those mutated in BRCA1/2.
Applicant 19
Name: Dr. Maria Angeles Juanes
Institution: Centro de Investigacion Principe Felipe (CIPF)
Project Title: A Novel Natural Small Molecule Inhibitor (SMI) in the treatment of Metastatic Colorectal Cancer
General Audience Summary: Half of colorectal cancer (or bowel cancer) patients suffer from cancer spread to other sites away from the colon such as the liver or lungs at the time of diagnosis, known as metastasis. Current therapies do not cure most of the metastatic cancer cases, but rather ameliorates its symptoms, implying the need for new therapies. We have discovered a new hope for bowel cancer patients: an interesting natural compound that specifically kills metastatic cancer cells without harmful effects on healthy cells. Here, we will further investigate the anticancer effects of this new molecule alone and/or in combination of current anticancer therapies. Our goal is to bring a new hope for those cancer patients.
Scientific/Technical Abstract: About 50% of colorectal cancer (CRC) patients show metastases in the liver, lungs or brain at the time of diagnosis. mCRC has a poor prognosis and in most cases, remains a non-curable disease. Available treatments such as chemotherapy only improves the cancer symptoms, and surgery is not possible in most mCRC cases due to the involvement of distal organs such as the brain. Therefore, there is an urgent need to have more efficacious drugs to cure mCRC. We have identified a novel natural small molecule that showed specific anticancer actions in mCRC cells without detrimental effects on healthy cells. Importantly, the novel natural compound significantly downregulated KRAS protein levels, a protein that is mutated in half of mCRC cases. We aim to discover effective therapies for mCRC patients. Specific aims are: (1) Define the molecular mechanisms underlying the anticancer activities of the novel small molecule in mCRC cells. (2) Investigate the efficacy and safety of the novel molecule as a monotherapy and/or combined with 5000 FDA-approved therapies in 2D/3D preclinical mCRC models. (3) Assess the selectivity of the novel molecule towards KRAS mutant in vivo mice models generated by CRISPR/Cas9 technology. These cancer genetics and biology aims are in line with the mission of the Concern Foundation.
Applicant 20
Name: Dr. Yuan-Hung Lo
Institution: University of Texas MD Anderson Cancer Center
Project Title: Unveiling the impact of epigenetic regulators on cell state dynamics in gastric tumorigenesis
General Audience Summary: We are trying to understand why some early cancer signs turn into full-blown cancer. Our bodies have natural controls to keep things in order, but cancer disrupts these controls. This disruption leads to changes in our cells, making cancer hard to treat. We are using stomach cancer as an example because it changes a lot at the early stage. We are looking are epigenetic regulators, which play a crucial role in this process. Our goal is to figure out the genetic reasons behind these cellular changes and find ways to stop cancer from starting. This could lead to new and better treatments for cancer.
Scientific/Technical Abstract: We aim to answer a long-term mystery — What underlying mechanisms prevent the progression of gastric precancerous lesions into malignancy? Under physiological conditions, intrinsic signaling pathways control gastrointestinal stem cell activity and guide stem cells toward specific cell lineages, thereby maintaining the homeostasis of the epithelium. This delicate balance is often disrupted during cancer development, leading to dynamic changes in cell states. These alterations in cell states are crucial in driving tumor development and contributing to the heterogeneous nature of malignancy. As a result, they significantly impact the response of cancer cells to existing therapies, ultimately leading to unfavorable clinical outcomes. However, our understanding of the impact of cell state changes on cancer development, and the potential of targeting a specific cell state for treatment remains limited. Here, we focus on epigenetic regulators as they have emerged as crucial contributors to gastric tumorigenesis, with high mutation rates observed in cancer patients. We hypothesize that dysregulated epigenetic regulators promote the transformation of normal epithelial cells by inducing them to the entry of a shared aberrant cell state. By unraveling the genetic driving force and defining these abnormal cell states, we aim to unveil the molecular mechanism underlying cell state dynamics to prevent cancer initiation and unearth novel therapeutic strategies.
Applicant 21
Name: Dr. Ofer Shoshani
Institution: Weizmann Institute of Science
Project Title: Determining the role of transient p53 inactivation in oncogene amplification biogenesis
General Audience Summary: Recent DNA sequencing efforts revealed that catastrophic genomic events in which chromosomes shatter and randomly reassemble are frequent across many cancer types. Our recent work showed that such catastrophic events drive the formation and evolution of gene amplification, an increase in DNA copies of pro-tumorigenic genes, an event frequently observed in many types of cancer. Normally, cells have multiple safeguards to prevent the formation of gene amplification, with the p53 protein acting as the main guardian of the genome. Here, we aim to study how gene amplification develops unnoticed, and focus on the role of p53 in this process. This work will provide insight on how chromosome aberrations develop and contribute to cancer formation and progression. Ultimately, this will lead to identification of specific vulnerabilities that could serve as targets for anti-cancer therapy.
Scientific/Technical Abstract: DNA amplification of oncogenes such as EGFR, MDM2, MYC, ERBB2, CCND1, among many others, is a major driver in more than half of all cancer types and is correlated with poor prognosis. We recently uncovered that chromothripsis, the catastrophic shattering of a chromosome with subsequent random rearrangements, is a major driver of gene amplification formation and evolution in cancer. It was previously suggested that p53 inhibits chromothripsis and gene amplification. However, many cancers present amplifications of key p53 regulators, such as MDM2 and MDM4. It was further found that such amplifications and mutations in p53 are often mutually exclusive. This raises the question: How could MDM2 or MDM4 undergo amplification in a p53 proficient background? Here, we propose that transiently reduced p53 activity could permit the amplification of MDM2 or MDM4, which, in turn, would completely shut down p53 activity. To address this, we aim to develop a sophisticated cell culture model that would allow examination of the role of p53 in critical steps leading to gene amplification. We will complement this effort by studying the role of p53 in the development of gene amplification in mice. This work will uncover the role of p53 and DNA breaks in promoting catastrophic events such as chromothripsis and gene amplification. Ultimately, this will establish new experimental models that will enable future studies of oncogene amplification biogenesis, and potential novel therapy design.
Applicant 22
Name: Dr. Katelyn Byrne
Institution: Oregon Health and Science University
Project Title: Reprogramming suppressive regulatory T cells in the tumor microenvironment
General Audience Summary: Leveraging the immune system to destroy tumor cells is a major goal of cancer immunotherapy. T cells are the immune cells able to identify and kill tumor cells. Current immunotherapies promote the activation and function of killer T cells, and have revolutionized medical oncology care; however, the vast majority of patients do not respond to current treatments. Suppressive T cells, called Tregs, normally aid the tumor, but reprogramming Tregs promotes killer-like T cells with the simultaneous loss of Tregs. Here, I propose to investigate reprogrammed Tregs in the context of pancreatic cancer, to identify the importance of these cells in contributing to tumor destruction.
Scientific/Technical Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an immunotherapy-resistant tumor type and the third leading cause of cancer-related deaths in the U.S., highlighting the need for improved treatment options. One such barrier is regulatory FoxP3+ CD4 T cells (Tregs), a subset of T cells that restrain effector T cells normally induced by immunotherapy. Recent reports show that Tregs can be ‘reprogrammed,’ and to our surprise, CD40 agonism (which ligates dendritic cells (DCs) to activate effector T cells) also results in a striking reduction in intratumoral Tregs. FoxP3-lineage tracing mice reveal that CD40 agonism promotes the loss of FoxP3 expression by Tregs, resulting in ‘ExTregs.’ The functional impact of these ExTregs and the mechanisms by which they are generated, remain to be elucidated. Here, we hypothesize that CD40 agonism on DCs in the PDAC TME promotes DC-Treg interactions to drive the generation of ExTregs that function to control PDAC via production of the anti-tumor cytokine interferon (IFN)-𝛾. These studies will reveal the underlying biology of CD4 T cell plasticity in the TME and would significantly shift our interpretation of Tregs in the TME, rendering Tregs a therapeutic opportunity instead of a barrier to tumor control.
Applicant 23
Name: Dr. Isabel Calvo
Institution: FOUNDATION FOR APPLIED MEDICAL RESEARCH (FIMA)
Project Title: A systems biology approach based on Single Cell multi-omic technology to understand the role of the Bone Marrow microenvironment in the pathogenesis of multiple myeloma
General Audience Summary: Multiple myeloma (MM) is a cancer that forms in a type of white blood cell called a plasma cell (PC) in which there is an abnormal proliferation of these cells leading to multi-organ damage. All MMs are preceded by an asymptomatic phase called monoclonal gammopathy of uncertain significance (MGUS). The process of tumor formation and progression from MGUS to MM is not only influenced by its parenchymal composition but also by the mesenchymal components (microenvironment) and the interconnection between them. Therefore, we propose to define the heterogeneity of the malignant microenvironment components to identify possible therapeutic targets for the treatment of this pathology, despite its consideration as an incurable disease in its advanced stage.
Scientific/Technical Abstract: Multiple myeloma (MM) is a type of bone marrow (BM) cancer, in which there is an abnormal proliferation of the plasma cells. Despite significant advances in the treatment of MM patients, most patients eventually relapse and cannot be cured. All MMs are preceded by an asymptomatic phase called monoclonal gammopathy of uncertain significance (MGUS). The process of tumor formation and progression from MGUS to MM is not only influenced by its parenchymal composition but also by the mesenchymal components (microenvironment) and the interconnection between them. Fortunately, today we have a big opportunity with the advent of single-cell sequencing, spatial profiling, and computational tools that allow us to reveal the cellular composition and gene regulation in tissues with unprecedented resolution. Thanks to the use of these technologies, the goal of this project is to characterize and functionally validate not only the cellular heterogeneity of BM microenvironment cells but also how these cells are spatially oriented to one another and the tumor-tissue interactions with the help of spatial transcriptomics and computational biology, that may constitute vulnerabilities with preventive/curative potential for a nowadays-fatal disease. These results will represent a unique opportunity for the identification of mechanisms that participate in the development and progression of MM from asymptomatic stages to clinically active MM.
Applicant 24
Name: Dr. Hua Zhang
Institution: University of Pittsburgh
Project Title: Combining CDK7 and WEE1 inhibition to target small cell lung cancer
General Audience Summary: Small cell lung cancer (SCLC) is one of the deadliest human cancers, accounting for about 15% of all lung and an estimated 250,000 death worldwide yearly. Although SCLC patients often initially respond to chemotherapy, tumors nearly always recur within 6 to 12 months. Treatment regimens for SCLC have remained largely unchanged for the past decades, highlighting the critical need for identifying new targets and treatment paradigms. In this work, we aim to utilize new selective inhibitor/degrader targeting oncogenic proteins named CDK7 and WEE1 and evaluate their anti-cancer effects in multiple murine SCLC models. Our work will provide strong evidence to support the combinatorial application of CDK7 and WEE1 inhibition in future clinical trials.
Scientific/Technical Abstract: Small cell lung cancer (SCLC) is designated as a recalcitrant disease with a five-year relative survival rate of less than 7% and an estimated 250,000 death worldwide yearly. Treatment regimens remain largely unchanged in the past few decades in SCLC, highlighting the critical need for identifying new targets and treatment paradigms. CDK7 and WEE1 are central regulators of transcription, cell cycle and antitumor immunity. Indeed, recent studies from our group and others showed that SCLC is extremely vulnerable to CDK7 and WEE1 inhibition. Given their important and complementary roles in regulating common oncogenic dependencies, we hypothesize that combining CDK7 and WEE1 inhibition will suppress tumor growth in SCLC. Herein, we aim to leverage our state-of-the-art preclinical platform to investigate the therapeutic potential of combining CDK7 and WEE1 inhibition in targeting SCLC. Utilizing new CDK7 inhibitor YKL-5-124 and WEE1 degrader ZNL-02-096, our preliminary data revealed combining YKL-5-124 and ZNL-02-096 offers a synergistic effect in human SCLC cells in vitro and in a mouse model. Herein, we will further evaluate the therapeutic efficacy of this combination in multiple novel syngeneic models and examine pharmacodynamic immune response to the treatment. Ultimately, characterizing the underlying mechanism will help develop tailored treatment for SCLC patients.
Applicant 25
Name: Dr. Alison Ringel
Institution: Massachusetts General Hospital
Project Title: Targeting CD226 loss on aged T cells to improve cancer immunotherapy
General Audience Summary: Immune therapy is a type of cancer treatment that stimulates the immune system to fight tumor cells. Since aging weakens the immune system, we think that the reasons why immune therapies fail may differ in younger or older cancer patients. We have identified a surface receptor critical for T cell functionality that is progressively lost during aging. Within tumors, aging expands the number of CD8+ T cells that have lost this receptor, and we identify distinct hallmarks of dysfunction within this population of T cells. The proposed studies will test the hypothesis that loss of this receptor can be targeted to improve responses to immune checkpoint blockade in elderly patients with cancer.
Scientific/Technical Abstract: Aging is a complex and multifaceted process that is closely linked to the development of cancer. The function of the adaptive immune system declines dramatically over lifespan, including major changes to the T cell pool that can recognize and kill cancer cells. However, it is still unclear what impact these differences have on patient outcomes following treatments that boost anti-tumor T cell responses. In preliminary studies, we have found that syngeneic tumors grow more rapidly in aged versus young adult mice and that aged animals fail to respond to immune checkpoint blockade therapy. Within tumors, we find that aging expands a distinct population of CD8+ T cells that have lost surface expression of CD226, an activating receptor critical for T cell effector function and tumor killing. Furthermore, aged CD226-low T cells are specifically enriched for hallmarks of exhaustion. We therefore hypothesize that aging leads to unique states of T cell dysfunction inside tumors and, consequently, distinct mechanisms of resistance to immunotherapy. The proposed aims will molecularly probe how aging remodels key effectors of the CD226 pathway in tumors (Aim 1) and then test whether treatments that enhance CD226 expression can improve responsiveness to immunotherapy in aged animals (Aim 2).
Applicant 26
Name: Dr. Christine Eyler
Institution: Duke University
Project Title: Interrogating PTEN epigenetic plasticity during treatment-induced rectal cancer evolution
General Audience Summary: About 40,000 people are diagnosed with rectal cancer per year in the US, often requiring aggressive treatments like chemoradiation and surgery. Many different factors determine which cells resist these therapies. Though genetic features contribute, some features NOT encoded in the DNA, called “epigenetic” features, also play a role. I aim to use several cutting-edge technologies to profile the mechanisms by which epigenetic controls regulate a key cancer gene called PTEN. These observations will potentially inspire new treatment approaches for patients with rectal cancer in order to maximize the efficacy of non-surgical treatments for patients while also minimizing toxicity from treatments.
Scientific/Technical Abstract: Locally advanced rectal cancer often necessitates chemoradiotherapy (CRT) and surgical removal of the rectum. Improvements in non-surgical treatments like CRT could augment disease control while potentially permitting strategic non-surgical treatment. Surprisingly, the mechanism by which treatments like CRT work remains unclear, and likely relates not only to genetic tumor features, but also to non-genetic (or epigenetic) regulation mechanisms. PTEN is a tumor suppressor gene with crucial epigenetic regulatory controls, and our preliminary data suggest that PTEN epigenetic regulation may drive CRT resistance. My group has developed an approach that permits ultra-high resolution epigenetic mapping of functional and topologic features governing the expression of genes like PTEN, including identification of specific contributing transcription factors. Using this approach, we have identified new epigenetic PTEN regulatory factors in colorectal cancer. We will apply this technique to characterize CRT-induced epigenetic PTEN alterations and identify key transcription factors involved. Additionally, we will implement a method I previously developed combining lineage tracing with single cell RNAseq to track how PTEN regulation affects CRT-induced evolution at the single cell level.
Applicant 27
Name: Dr. Michelle Teplensky
Institution: Boston University
Project Title: Raising Anti-Melanoma Immunity Via STING-activating Nanoscale Architecture
General Audience Summary: We will develop an innovative class of DNA-based nanostructures as immunotherapies against melanoma. Immunotherapies harness the body’s immune system and target it against melanoma. Stimulator of Interferon Genes (STING) is a promising immune-stimulating pathway, but drugs targeting it have done poorly in clinical trials. Our data attribute this to how they are seen by immune cells. We have shown that structural presentation has a dramatic impact on how drugs are processed and how effective an immune response can fight melanoma. This research develops platforms to deliver STING drugs in optimized ways to cells, and will provide a new path towards robust therapies that are broadly effective.
Scientific/Technical Abstract: Immunotherapeutics against melanoma must overcome barriers that prevent tumor remission. One promising pathway is activating the Stimulator of Interferon Genes (STING), a mechanism that promotes innate and adaptive immunity. STING agonists are clinically used to stimulate IFN-I and promote generation of T cell responses. However, response rates are low. This can be attributed to the: 1) inability to activate STING signaling in immune cells to counter an immunosuppressive tumor; 2) loss of STING signaling in tumor cells, hiding them from attack; and 3) lack of optimal agonist therapeutic delivery and persistence. We will develop DNA nanostructures to overcome these barriers and effectively deliver STING agonists to propagate antitumor immunity. The nanostructures avoid common pitfalls of other therapeutics, enabling them to revitalize existing agonists by improving delivery and presentation to cells. Critically, we have shown the essential role of nanoscale architecture in elevating the uptake of immune cues, synchronizing multifaceted interactions, and raising robust immunity. By harnessing nanoscale architecture to program signaling, we will overcome limitations and achieve potent antitumor immunity, providing a new path towards effective, rationally designed melanoma therapy.
Applicant 28
Name: Dr. Linghua Zheng
Institution: Ohio State University
Project Title: Targeting a New Immune Checkpoint Axis (PILRα–CD8α) to Treat Glioblastoma
General Audience Summary: Immunotherapy aimed at cell surface proteins has seen substantial success in clinical practice. Monoclonal antibodies that target anti-PD-1/PD-L1 have received approval from the FDA for treating around 20 different types of human cancer. However, it's worth noting that anti-PD-1 treatment isn't effective for glioblastoma patients. This underscores the urgent need to discover additional pathways that inhibit cancer immunotherapy for glioblastoma. We've recently uncovered a novel immune inhibitory pathway, which is mediated by the interaction between cell surface PILRα and CD8α. Our objective is to clarify its role in the treatment of glioblastoma.
Scientific/Technical Abstract: While T cell checkpoint inhibitors like anti-CTLA-4 and anti-PD-1 monoclonal antibodies (mAbs) have revolutionized cancer therapy, glioblastoma patients have demonstrated resistance to this form of therapy. PILRα is exclusively and abundantly expressed on the cell surface of myeloid cells, whereas CD8α is consistently present on the surface of lymphocytes. Through genetic deletion and antibody blockade, we've discovered that PILRα–CD8α interactions can transmit an inhibitory signal to CD8+ T cells, keeping them in a quiescent state in the absence of exposure to antigens. Additionally, in a model of antigen(peptide)-induced CD8+ T cell tolerance, blocking PILRα–CD8α interactions with anti-PILRα mAb effectively prevents the induction of CD8+ T cell tolerance. Moreover, the use of anti-PILRα mAb as a treatment shows promise in extending the survival of mice that have been injected with glioblastoma cell lines. In this proposal, we aim to evaluate the therapeutic impact of single anti-PILRα mAb treatment and combination therapy in the context of glioblastoma treatment. We will also delve into the underlying mechanisms responsible for these effects.
Applicant 29
Name: Dr. Yaron Antebi
Institution: Weizmann Institute of Science
Project Title: The Combinatorial Effect of Signals on Epithelial-Mesenchymal Transition in Cancer
General Audience Summary: Cancer is a complex disease, posing significant challenges to understand and treat efficiently. Our focus is on a process called Epithelial-Mesenchymal Transition (EMT), which plays a crucial role in cancer's progression and resistance to treatment. We're exploring how combinations of signals in the body influence EMT and drive cancer's spread. Our research plan involves investigating genetic changes, how cancer cells behave, and building predictive models. By uncovering the mysteries of EMT and its signaling, we're paving the way for smarter, more personalized cancer treatments, aiming for precise and effective therapies that target multiple cancer pathways simultaneously.
Scientific/Technical Abstract: Epithelial-Mesenchymal Transition (EMT) is a pivotal process in cancer progression, which empowers cancer cells with metastatic potential, therapeutic resistance, and immune evasion. Signaling pathways activated by the tumor microenvironment play an essential role in determining the development of EMT traits. However, the combinatorial complexity of signals has impeded our ability to fully understand the regulatory role of the environment on EMT and to predict specific therapeutic interventions from basic principles. Here, we propose to investigate the impact of combinatorial signaling environments on EMT decisions in carcinoma cell lines across a comprehensive array of signals. Using high throughput techniques, we will collect genetic and phenotypic information from cells exposed to hundreds of different signaling environments over time and analyze the EMT decisions that cells make. Furthermore, we will develop predictive mathematical models that encompass intra- and extra-cellular regulation, aiming for a predictive understanding of the cross-talk between signals. Ultimately, we aim to decipher how cancer cells can be guided away from malignancy through the use of signals, enabling the development of more precise and targeted cancer treatments.
Applicant 30
Name: Dr. Alvaro Teijeira
Institution: CIMA, Universidad de Navarra
Project Title: XPMET: Antigen crosspriming in lung cancer metastases
General Audience Summary: Most lung cancer patients die because of complications derived from the presence of metastasis. In lung cancer, the approval of a new type of cancer therapy aiming to activate the patient's immune response to eliminate cancer cells (immunotherapy) has revolutionized disease management and survival rates. However, many patients do not benefit from such therapy, especially metastases in many organs that do not respond to these treatments. Dendritic cells are a particular cell type of our immune defense that can recognize tumors as pathogenic and activate lymphocytes that can recognize and kill such cancer cells. We aim to investigate how these dendritic cells are important in controlling lung cancer metastases and develop new therapies to boost the functions of such immune cells. Our final goal is to expand the number of patients that benefit from approved immunotherapies for lung cancer allowing the best immune responses against the metastatic cancer cells.
Scientific/Technical Abstract: Metastasis is the main leading cause of death in lung cancer. Despite the success of cancer immunotherapy in advanced lung cancer, metastases are often resistant to immune checkpoint blockade and show limited response to immunotherapy. Very little is known about the setup of tissue-specific anti-tumor immune responses against metastatic sites. The key importance of dendritic cell infiltration and antigen crosspriming in tumors has been highlighted by several studies indicating that infiltration of dendritic cells in human cancer and mouse studies is needed to allow a proper response to current immunotherapies. Our project aims to define if antigen crosspriming dendritic cells and antigen crosspriming itself is important to set immune responses in the metastatic sites targeted by lung cancer. Using several lung cancer cell lines and both systemic and orthotopic models of bone, adrenal gland, liver, and brain metastases we will decipher if cDC1 cells and crosspriming are needed to generate a proper antitumor immune response and impair metastatic spread. We will develop new therapeutic strategies based on mRNA systemic delivery to allow cDC1 cell expansion and combine it with checkpoint blockade and TLR agonists in preclinical models to achieve systemic immune responses against difficult-to-treat established metastases.
Applicant 31
Name: Dr. Federico Lucantoni
Institution: Príncipe Felipe Research Center Foundation (CIPF)
Project Title: RES-Ento: dissecting the role of entosis during treatment resistance in ER+ breast cancer
General Audience Summary: Entosis is a process where one cell enters another cell of the same type. This happens in certain types of cancer and can make tumors more aggressive. When one cell enters another, it can either get away, divide and leave, or, in most cases, get degraded by the host cell. The cells that get "digested" by the host cells become a source of nutrients for the host cells. We've discovered that a drug called Palbociclib, used to treat certain breast cancers, can make some cancer cells undergo entosis. Our goal is to study this in detail using advanced microscopes, genetic techniques, and lab experiments in both flat and 3D cultures, as well as in animal models. Ultimately, we want to show that entosis is a way that breast cancer can resist treatment.
Scientific/Technical Abstract: Entosis is a homotypic invasion mechanism in which one cell infiltrates another cell of the same type. This process has been identified in several malignancies and has been linked to the aggressiveness of solid tumors. Once a cell has entered another, it may either escape, divide and exit, or, as is the case in the majority of instances, undergo a lipidation-dependent pathway known as entotic cell death. Cells capable of escaping are partially protected by the immune system's activity or systemic chemotherapeutic treatments. However, cells that are "digested" by host cells serve as a source of genetic material and nutrients, which can nourish the host cells. We have discovered that Palbociclib, a CDK4/6 inhibitor used in the treatment of specific breast cancer types, induces entosis in a subset of cancer cells. The objective of this project is to comprehensively characterize Palbociclib's ability to induce entosis using advanced microscopy techniques, omics methods, and cell/molecular biology assays in both 2D and 3D cultures, as well as in in vivo models. Ultimately, we aim to establish entosis as a mechanism of treatment resistance in the context of breast cancer.
Applicant 32
Name: Dr. Dennis Jones
Institution: Boston University Chobanian and Avedisian School of Medicine
Project Title: Improving vascular function to enhance cancer-specific T cell entry into solid tumors
General Audience Summary: T cells can kill cancer cells, but only if they have access to the tumors; blood vessels usually play a crucial role in facilitating this process. However, we found that tumor growth can compress blood vessels and impair their ability to move T cells into tumors. We will test the hypothesis that decompression of blood vessels enhances cancer-specific T cell entry into tumors and that immune therapy can boost the function of infiltrated T cells to decrease tumor burden.
Scientific/Technical Abstract: We’ve recently shown that physical forces from tumors, known as solid stress, compress blood vessels to deny T cell entry. Treatment of animals with losartan, an FDA-approved drug that reduces extracellular matrix production, increased the presence of T cells in lymph node breast tumors. Based on these findings, we propose to test the hypothesis that decompressing the tumor vasculature with losartan improves blood vessel function in advanced breast tumors. In our mouse breast cancer models, we will utilize an imaging window that facilitates long-term observation of tumors. This window will enable us to evaluate blood vessel functionality, track cancer-specific T cell entry into primary breast tumors, and monitor the accumulation of solid stress in vivo. Further, our animal experiments will uncover whether losartan, combined with immune checkpoint inhibitors that can enhance T cell function, eradicates breast tumors.
Applicant 33
Name: Dr. David Sykes
Institution: Massachusetts General Hospital
Project Title: Targeting tumor associated macrophages for the treatment of prostate cancer bone metastases
General Audience Summary: Prostate cancer (PCa) is highly curable when identified early. However, when PCa has spread to the bones it is a deadly disease that causes side effects like pain and fractures. Our research focuses on bone metastases. PCa can survive within the bone marrow by corrupting immune cells called tumor associated macrophages (TAMs). We hope to target these TAMs as one approach to eradicating bone metastases. This proposal builds on 7 years of foundational research with a team of surgeons, oncologists, pathologists, and biologists. Our work includes a new cell line and new mouse model that will facilitate research into identifying new treatments for patients with cancer bone metastases.
Scientific/Technical Abstract: Castrate-resistant bone metastatic prostate cancer is a morbid and deadly disease. Bone metastases are challenging to model in the laboratory and therapies that specifically target metastases are limited in availability and efficacy. Our team has spent the last 7 years processing fresh patient prostate cancer samples from bone metastases (Cancer Cell, 2021) and primary prostatectomies (Nature Communications, 2023). These studies, and other preliminary data, have consistently pointed to dysregulated myeloid populations including tumor associated macrophages (TAMs) as key drivers of disease progression. In this Concern Foundation proposal, we will use a new and genetically tractable myeloid model to specifically interrogate the mechanistic role of five key pathways in the immune suppressive role of TAMs. Isogenic lines will be established to study TREM2, MSR1, APOE, SYK, and MERTK. We will further use these isogenic lines and a new syngeneic mouse model of aggressive bone metastases to assess their effect in vivo. This model system will also allow us to quantify the effect of the different modified TAMs on the response to anti-PD1 immunotherapy as a pre-clinical rationale for potential new TAM directed therapies for cancer patients with bone metastases.
Applicant 34
Name: Dr. Shengquing Gu
Institution: MD Anderson Cancer Center
Project Title: Novel CAR-T therapy for acute myeloid leukemia
General Audience Summary: Acute myeloid leukemia (AML) is one of the most common types of leukemia, a cancer of the blood and bone marrow. Standard treatment involves chemotherapy and stem cell transplantation, but most patients develop resistance and succumb to this disease. Immunotherapy can kill cancer cells by detecting antigens found on cancer cells. CCNE1 is an AML-associated antigen that is highly abundant in AML cancer cells. This study will assess the efficacy of an immunotherapy that targets CCNE1 for AML therapy, providing a novel approach to improve patient outcomes.
Scientific/Technical Abstract: There is an urgent unmet need for more effective therapies for acute myeloid leukemia (AML). Immunotherapy directed at AML-associated antigens is a promising treatment strategy to eliminate cancer cells and limit adverse toxicity. CCNE1 is a cancer-associated gene that is highly expressed in AML. CAR-T cells that target HLA-A2-presented CCNE1 peptide can respond to HLA-A2+ CCNE1- expressing cancer cells. However, the efficacy of CCNE1-targeting CAR-T cells in AML is unclear. We hypothesize that CCNE1-targeting CAR-T therapy can effectively target AML cells and propose to assess the efficacy of this therapy in AML using cell lines and primary patient samples. We will examine the cytotoxic effects of CCNE1-targeting CAR-T cells first in human AML cell lines and then in primary AML patient samples. If successfully completed, this study can reveal whether CCNE1- targeting CAR-T therapy can effectively eliminate AML cancer cells and has the potential to introduce a novel therapeutic strategy for AML. This project will also lay the foundation to further devise combination immunotherapeutic strategies for AML as an R01 application.
Applicant 35
Name: Dr. Mary Sewell-Loftin
Institution: University of Alabama at Birmingham
Project Title: Investigations of Mechanosignaling in Triple Negative Breast Cancer Progression
General Audience Summary: Triple negative breast cancer (TNBC) has high incidences of metastasis and is regulated by biomechanical processes; however current drug strategies do not inhibit mechanical regulation of tumor cell behaviors. The overall objective of this proposal is to understand how cancer-associated fibroblasts create active biomechanical forces in the tumor microenvironment to regulate signaling in TNBC related to metastasis and growth. The proposed studies positively impact the cancer research community by advancing the scientific understanding of cancer progression and potentially provide novel strategies for improving cancer treatments by targeting mechanobiological regulation of tumor progression.
Scientific/Technical Abstract: Little is known of how biomechanical forces alter the tumor microenvironment (TME) of triple negative breast cancer (TNBC) to promote disease progression. Specifically, the role of cancer-associated fibroblast (CAF) generated strains or matrix distortions as mechanical cues is largely unknown. VEGFR-2 expression in TNBC is correlated with worse overall survival, and traditional anti-VEGFR-2 drugs only inhibit soluble ligand/receptor interactions and not mechanosignaling. The central hypothesis for this proposal is that CAFs distort the matrix, leading to enhanced and altered VEGFR-2 signaling to drive increased tumor proliferation and migration. This will be tested through the following specific aims: (1) Determine the mechanism of biomechanical activation of the VEGFR-2 pathway in TNBC and (2) Determine how mechanical activation of VEGFR-2 by CAF-induced matrix distortions regulates TNBC migration and proliferation. Under the first aim, studies will interrogate how mechanical forces alter phosphorylation of VEGFR-2 in TNBC cell lines. The studies in Aim 2 will use a biomimetic tissue-engineered model of the TME that permits separation of mechanical from soluble/ligand cues to uncover mechanobiological regulation of TNBC progression. The research proposed in this research application is innovative and significant because it focuses on investigating mechanoregulation through VEGFR-2 as a novel mechanism of TNBC progression and will demonstrate that this is a targetable phenomenon.
Applicant 36
Name: Dr. Kaitlin Basham
Institution: University of Utah
Project Title: Androgen Regulation of Anti-Tumor Immunity in Adrenal Cancer
General Audience Summary: Differences between men and women can have a big effect on cancer risk and survival, but we don’t fully know why. Understanding how sex impacts cancer will help create cancer treatments that are more individualized and therefore more effective. Our studies focus on a deadly form of cancer in the adrenal gland that is more common in women. Our team discovered that this sex difference is linked to an underlying difference in the immune system. Men – who are less likely to get adrenal cancer – have a stronger immune response that clears away pre-cancerous cells. We also found that male sex hormones called androgens, which include testosterone, enhance this protective immune response. Our goal is to figure out how androgens regulate the immune system so that we can use sex hormones to optimize cancer therapy.
Scientific/Technical Abstract: Sex disparities significantly influence cancer outcomes, but the fundamental mechanisms are not well understood. Our studies focus on a routinely fatal cancer of the adrenal gland called adrenocortical carcinoma (ACC), which is ~2.5X more common in women than men. Our overarching goal is to exploit the unique sex bias in ACC to identify new treatment strategies. To achieve this, our lab developed a new genetically engineered mouse model of ACC that recapitulates the female sex bias. Using this model, we discovered that males – who have a lower incidence of malignant tumors – exhibit a stronger myeloid immune response preceding tumor development. Further, we found that androgen deprivation in males blocks the myeloid immune response and enhances adrenal growth. We translated these findings to humans by showing, 1) male ACC patients have a higher myeloid immune response than females, 2) a high myeloid response is associated with longer ACC patient survival, and 3) hypogonadal men with low androgen levels have an increased risk of ACC. Here, we hypothesize that androgen deficiency increases adrenal cancer risk by impairing the recruitment and function of monocytederived immune cells. Using patient-derived samples and laboratory models, we will determine how androgens regulate both systemic immunity as well as the local adrenal microenvironment to help protect against cancer. This work will help advance efforts to increase the efficacy of immunotherapy by optimizing endocrine hormone levels.
Applicant 37
Name: Dr. Jason Hanna
Institution: Purdue University
Project Title: Targeting and investigating the regulation of the FOXM1-PLK1 axis in angiosarcoma
General Audience Summary: Angiosarcoma is an aggressive soft tissue cancer that develops from the cells lining blood and lymphatic vessels. Unfortunately, angiosarcoma is associated with a very poor prognosis and treatment options are limited due to the understudied nature of this tumor. In studying patient samples, cells, and in vivo models we have discovered an increase in abundance and activity of proteins called PLK1 and FOXM1 and a decrease in tiny RNAs called microRNAs. Here we will study how these proteins and microRNAs function and test the effectiveness of therapies targeting these molecules.
Scientific/Technical Abstract: Angiosarcoma is an aggressive tumor developing from endothelial cells with a dismal prognosis and limited treatment options. Recent sequencing efforts have identified some recurring mutations. However, for many patients the molecular drivers and actionable therapeutic targets remain unclear. We have generated mouse models of angiosarcoma that resemble human tumors histologically and genetically. These models are driven by the endothelial loss of Cdkn2a and activation of oncogenic Kras or through the conditional deletion of Dicer1, resulting in the loss of mature miRNAs. By integrating gene expression alterations in mouse and human tumors combined with studies in cell lines, we have identified hyperactivity of FOXM1 transcription, overexpression of PLK1, and the loss of miR-497 as key alterations in AS. In Aim 1 we will determine the contribution of PLK1-FOXM1 in tumorigenesis. Aim 2 will determine the miRNA regulatory network in angiosarcoma and test the therapeutic efficacy of miR-497 replacement. The outcomes of this research will significantly contribute to our knowledge of underlying mechanisms driving angiosarcoma while also providing key evidence for the therapeutic targeting of this critical signaling axis.
Applicant 38
Name: Dr. Hugo Gonzalez
Institution: Fundacion Ciencia y Vida
Project Title: Reprogramming of the Metastatic Niche by Tumor Cell-Derived Factors
General Audience Summary: Metastatic breast cancer is challenging, causing most cancer-related deaths. Our team studies cancer cells for over seven years, now we are focusing on the MIF gene's role in breast cancer. We plan experiments to understand how MIF supports metastatic tumor growth. Our primary goal is to explore MIF's impact on the microenvironment during metastasis, aiding cancer cell spread and evasion. With Concern Foundation funding, we aim to address clinical needs of metastatic breast cancer patients by accelerating our research on the tumor-host interface.
Scientific/Technical Abstract: Metastasis causes over 90% of cancer-related deaths, marked by altered cancer cells, enhanced plasticity, and immune evasion. Our 7-year research focuses on metastatic tumor cells (MTC) in humans and the tumor-host interface. With recent insights from single-cell genomics, we aim to understand how MTC-derived MIF impacts the metastatic niche. We believe MIF plays a crucial role in reprogramming the microenvironment for metastasis. Using mouse models and single-cell analyses, we propose three specific aims: Specific Aim 1. Characterization of the effect of MTC-derived MIF on the formation of the TME in experimental breast cancer brain, bone, and lung metastasis. Specific Aim 2. Characterization of the transcriptomic programs and cell states induced on the TME by MTC-derived MIF in vivo. I Specific Aim 3. Impact of therapeutic intervention targeting the metastatic niche to eliminate metastatic tumors. Our research explores how MTCs reprogram the microenvironment to promote metastasis and the potential for therapeutic intervention. This work delves into the intricate molecular mechanisms of malignant cell reprogramming and its interaction with non-malignant stroma, offering new avenues for cancer therapy.
Applicant 39
Name: Dr. Anja Karlstaedt
Institution: Cedars-Sinai Medical Center
Project Title: Metabolic Determinants of Colorectal Cancer
General Audience Summary: Colorectal cancer is the second leading cause of cancer death in the United States, and improved therapies are sorely needed. Patients frequently present with cardiovascular problems upon cancer diagnosis. Recent data indicates that shared metabolic risk factors may contribute to disease progression. Using preclinical models of colorectal cancer, we found that alterations in cardiac lipid metabolism increase tumor growth. We suspect that changes in the metabolism of the heart influence tumor growth by limiting an immune response. Our project will study how these cell-cell interactions occur using animal models and with data from a human colorectal cancer cohort.
Scientific/Technical Abstract: Colorectal cancer (CRC) remains one of the deadliest cancers in the United States. Individuals harboring metabolic risk factors for cardiovascular diseases, such as obesity and diabetes, have a three times higher risk of developing CRC. A transient immune cell activation characterizes cardiovascular diseases and cancer. A better mechanistic understanding of systemic metabolic changes that drive CRC progression is desperately needed. In preliminary studies, we found that the enzyme ATP-dependent citrate lyase (ACL) drives a metabolic crosstalk between cancer cells and the heart. We hypothesize that changes in cardiac metabolism trigger an immunosuppressive phenotype supporting tumor growth. Aim 1 will quantify cancer cell-specific metabolic changes in response to the loss of ACL in the heart. Aim 2 will determine how changes in lipid metabolism support CRC growth by altering the immune response. We will use targeted metabolomics and in vivo tracer studies to quantify the metabolic fate of nutrients. Our studies will be supported by mathematical modeling and human cohort data derived from the ColoCare study. Our proposed study offers a unique opportunity for cross-disciplinary interaction between a diverse team of cardiology and oncology experts to improve care for CRC patients.
Applicant 40
Name: Dr. Nan Zhang
Institution: The Wistar Institute
Project Title: Myeloid cell-derived interleukin 1b promotes chemoresistance in metastatic ovarian cancer
General Audience Summary: In 2023, it is estimated that 19,710 women will be diagnosed with ovarian cancer, and 13,270 women will die of ovarian cancer in the United States. Most ovarian cancer patients respond very well to the frontline chemotherapy, but the majority of them will ultimately succumb to chemoresistant relapse. How chemoresistance develops after the front-line therapy is not known. Studying this process will facilitate the development of therapies against chemoresistant ovarian cancer, saving many lives and families. In the current proposal, we will investigate how chemotherapy activates certain white blood cells to release an inflammatory protein (interleukin 1b) to promote chemoresistance.
Scientific/Technical Abstract: Most ovarian cancer (OC) patients respond to the front-line chemotherapy but succumb to chemoresistant relapse with peritoneal metastases. How chemoresistance develops in OC patients after the front-line chemotherapy remains poorly understood. Recent understanding of the tumor immune microenvironment (TIME) suggests that inflammatory mediators from myeloid cells play key roles in developing chemoresistance. This proposal seeks to understand whether and how a classical inflammatory mediator from myeloid cells, interleukin 1β (IL1β), promotes OC chemoresistance, aiming to eradicate metastatic OC by overcoming IL1β-mediated chemoresistance. Based on published and our preliminary results, we hypothesize that myeloid cell-derived IL1β promotes chemoresistance in metastatic OC by modifying TIME via activation of OC cells and fibroblasts; combining IL1β neutralization and chemotherapy eliminates chemoresistant OC. This will be tested with the following Aims. Aim 1: Test the hypothesis that the combination of chemotherapy and IL1β neutralization overcomes OC chemoresistance. Aim 2: Test the hypothesis that myeloid cell-derived IL1β drives OC chemoresistance by modifying TIME. Aim 3: Test the hypothesis that myeloid-derived IL1β promotes formation of chemoresistant spheroids.
Applicant 41
Name: Dr. Laura Mondragon
Institution: Josep Carreras Leukaemia Research Institute
Project Title: Defects in caspase independent cell death processes at the root of T cell lymphoma development
General Audience Summary: Angioimmunoblastic T cell lymphoma (AITL) is a rare blood malignancy which affects elder people and does not present symptoms till late stages of the disease. At present, there are no treatments to cure it and only 3 out of 10 patients live 5-years after diagnosis. We studied two mouse models which present the same disease than human, we consider defects in the way cells undergoes cell death can be the cause of AITL appearance. We would find drugs that restore this cell death processes and we will validate this strategy testing their effect in our animals and patient’s samples. In this way, we would like to provide better therapies to treat AITL patients’ and increase their survival chances.
Scientific/Technical Abstract: Angioimmunoblastic T-cell lymphoma (AITL) is a lymphoma characterized by a sudden onset of symptoms, detection on phases III/IV and a 5-years survival of 32%. It is originated by permanently active follicular T-helper (Tfh). There is still no clear definition of the genetic and phenotypic pattern for AITL, which prevents a proper diagnosis and therapy development. We have characterized two animal models: plck-GAPDH and Apaf-1+/-. GAPDH overexpression and Apaf-1 downregulation led to the same mice phenotype similar to AITL. Considered that: a) GAPDH and Apaf-1 modulation have a cytoprotective effect in the context of caspase-independent cell death and apoptosis; and b) the fact that Tfh remain active after immune response shutdown (a process leading to the death of most of active T cells), a cause for AITL origin could be defective cell death processes preventing Tfh elimination. We will develop genomic studies to identify defects in cell death pathways in tumoral vs healthy samples from mice and patients. With the potential targets identified, chemical libraries screening will be performed to restore cell death processes in these tumoral Tfh. Subsequent in vivo validation of the drugs identified employing PDXs of mice and patients will be done.
Applicant 42
Name: Dr. Stephanie Markovina
Institution: Washington University in St Louis
Project Title: Targeting mechanisms of tumor immune evasion in cervical cancer
General Audience Summary: Cooperation from the patient’s immune system is critical to curing human cancer. Tumors have many ways to evade the immune system. These include active suppressive signals that inhibit the activity of antitumor T cells, exploit the built-in editing systems that prevent autoimmunity, and promote inflammatory signals that function to confuse the immune system. The overall goal of this innovative proposal is to determine if tumor cell expression of a protein called SERPINB3 represents a novel mechanism of immune evasion, and if this process can be targeted with existing drugs that will improve immune cooperation and increase the chance of cure with standard therapies.
Scientific/Technical Abstract: Recurrence after definitive chemoradiation therapy for cervical cancer occurs in 30%-50% of patients, and most of these patients die as a result of ineffective salvage therapies. An improvement in survival in patients with recurrence or metastasis was recently reported with anti-PD1 immune checkpoint therapy, providing proof of principle that targeting immune checkpoints is a valid therapeutic approach for cervical cancer. Identifying common mechanisms of immune evasion specific to this disease is critical. Our published data suggest that SERPINB3 is commonly overexpressed in cervical and other carcinomas, and that high levels of expression are associated with disease recurrence and death. Our recently published data demonstrate that SERPINB3 also contributes to an immuno-suppressive tumor milieu, promoting expression of myelo-attracting chemokines and suppressing T cell activity. Based on unpublished preliminary data presented herein, we hypothesize that SERPINB3 directly interacts with factors along the MAPK and JAK/STAT pathways, leading to pathway activation that mutes the anti-tumor immune response and the response to radiation. We propose to identify the precise mechanism by which SERPINB3 promotes MAPK/STAT activation in order to develop innovative therapies that block this specific function. Furthermore, we will test the hypothesis that SERPINB3 expression is a predictive biomarker for response to myeloid-cell targeting therapies that synergize with radiation to improve tumor control.
Applicant 43
Name: Dr. Marianne Burbage
Institution: Institut Curie
Project Title: Control of TE exonisation and tumor immunogenicity by the splicing machinery
General Audience Summary: Identifying strategies to boost immune responses to cancer is long-standing goal for clinicians and immunologists. One promising strategy is to develop cancer vaccines, but this requires identifying suitable targets. For long, researchers have looked for targets deriving from coding genes, that represent less than 2% of the genome. Several recent studies, including my latest work, show that tumor cells also express targets derived from non-coding genomic regions that can be targeted by immune responses. In this project, I propose to further explore these targets from the non-coding genome to identify novel therapeutic opportunities to treat cancers.
Scientific/Technical Abstract: Understanding how the immune system detects and can be manipulated to detect tumour cells is a central question in immunooncology. Cancer cells can be detected by CD8 T lymphocytes via their T cell receptor that recognise peptides loaded on Major Histocompatibility Complex I. Identifying which tumour-specific antigens allow T cells to distinguish cancer cells from healthy ones is critical. Peptides derived from mutations acquired by tumour cells are a source of tumour antigens, but are often private to each patient. In addition, there is mounting evidence that “non-coding” regions of the genome, in particular transposable elements (TEs), can contribute tumour antigens. In my latest work, I showed that tumour-specific splice junctions between exons and transposable elements (JETs) are a source of recurrent, immunogenic, protective, and epigenetically regulated tumour antigens. Here, I propose to pursue the exploration of the mechanisms controlling JET formation with a focus on the splicing machinery. This project will characterize the splice sites that support JET formation, identify the splicing co-factors that regulate JET formation, and explore the therapeutic potential of targeting the splicing machinery to modulate tumor immunogenicity.
Applicant 44
Name: Dr. Megan Ruhland
Institution: Oregon Health & Science University
Project Title: Antigen sorting by dendritic cells impacts anti-tumor immunity
General Audience Summary: Dendritic cells (DCs) survey tissues for signs of disease. In tissues like the skin, a DC can engulf both a safe self-antigen and a dangerous antigen simultaneously. The DC needs to present the dangerous antigen for T cell activation but hide the self-antigen from T cell attack. We have identified distinct DC compartmentalization of safe and danger antigens finding safe proteins stored together and kept separate from danger antigens. We hypothesize that melanoma tumor antigen may be sorted as ‘safe’ rather than ‘danger’ thus blunting anti-tumor immunity. This proposal will study how DCs function in the tumor and identify new targets to optimize DCs for clinical benefit.
Scientific/Technical Abstract: The majority of immunotherapeutic agents target dysfunctional T cells. While directly engaging T cells has benefited many melanoma patients, others remain unresponsive to T cell-targeted approaches. Conventional dendritic cells (cDCs) are essential for generating T cell responses. Due to this critical function, cDCs are a promising target for immunotherapy. However, targeting cDCs has been largely unsuccessful. In the skin, cDCs are exposed to a diverse array of proteins including host-derived and those from the commensal skin microbiome (‘safe’) as well as the tumor and pathogens (‘danger’). Using fluorescent reporter tools to track antigen sources, we identified distinct cDC compartmentalization of antigens. We hypothesize that cDCs sort antigen into unique compartments that inherently impact presentation and anti-tumor immunity This proposal will (i) define the protein composition and maturation kinetics of antigen-specific endosomal compartments and (ii) determine the role of an antigen hierarchy in driving differential antigen presentation and T cell stimulation in cancer. This proposal seeks to address a critical gap in our understanding of cDC function and will ultimately provide the foundational cell biologic studies needed for new therapeutic targets.
Applicant 45
Name: Dr. Eric Nickels
Institution: Children's Hospital Los Angeles
Project Title: Identifying Early Genetic and Epigenetic Variants in the Pathogenesis of Acute Myeloid Leukemia Using Leukemia-Discordant Twins
General Audience Summary: While the cause of pediatric acute myeloid leukemia (AML) is not fully understood, it is likely to arise early in life in part due to genetic mutations and epigenetic influences that act outside the genetic code to control how genes are read. Through investigations before disease onset in twins where only one sibling develops AML in an otherwise genetically identical pair, we will analyze how early genetic and epigenetic changes lead to AML development. By identifying new features of early leukemia biology and discovering markers that can identify children at highest risk of disease, this study has the potential to impact prediction, risk management and improve outcomes in children with AML.
Scientific/Technical Abstract: Despite a deeper understanding of the molecular features of pediatric acute myeloid leukemia (AML) scientists have not fully elucidated its etiology. Genetic copy number variations (CNVs) and DNA methylation are critical at diagnosis, however their role as early contributing influences on AML progression remains to be described. While these alterations may go undetected in a genetically outbred population, studies in monozygotic twins, where one sibling develops AML and the other does not, provide a unique opportunity to investigate genetic and epigenetic influences on AML development. We hypothesize molecular variants identified in otherwise genetically identical twins drive pediatric AML progression. We aim to identify novel CNVs and DNA methylation variation contributing to AML pathogenesis using neonatal dried blood spots from monozygotic twins discordant for developing AML. We expect to identify novel molecular variants contributing to AML and will test the validity of our results in a non-twin AML cohort. This study’s impact is that newly identified molecular markers will enable earlier recognition of children at risk for AML, facilitating implementation of preventive screening and surveillance strategies and to identify preleukemic mutations that may contribute to relapse.
Applicant 46
Name: Dr. Vidyasagar Koduri
Institution: Brigham and Women's Hospital
Project Title: Characterization and Therapeutic Targeting of ZEB2- mediated Epigenetic Regulation of AML Cell Survival and Differentiation
General Audience Summary: Acute Myeloid Leukemia (AML) is a blood cancer in which genetic mutations in primitive blood cells interrupt normal maturation at an early stage (myeloblasts), and trigger the uncontrolled proliferation of the myeloblasts. Current treatments like chemotherapy and stem cell transplantation only provide a 30% chance of survival. My research is focused on the crucial role of ZEB2. ZEB2 is a protein that is necessary for keeping cell trapped at the myeloblast stage, and for the survival of myeloblasts. In this proposal, I first outline experiments to understand how ZEB2 acts to prevent myeloblasts from maturing. Secondly, I outline the adaptation of new drug-screening platforms to identify degraders ZEB2 that should kill AML cells.
Scientific/Technical Abstract: Current treatments for Acute Myeloid Leukemia (AML) offer a 5 year survival of 30%. New therapies are needed. AML is characterized by an arrested hematopoietic differentiation and uncontrolled proliferation of abnormal myeloblasts. I have identified the transcription factor ZEB2 as a promising target. ZEB2 is essential to AML cell survival, acts as a transcriptional repressor in AML cells, and binds to known co-repressor proteins (e.g. CtBP/LSD1/HDAC1). ZEB2 loss triggers myeloblast differentiation. I hypothesize that ZEB2 recruits co-repressor complexes to repress myeloid differentiation and survival genes. Understanding this process and targeting ZEB2 will help us develop new therapies in AML. In Aim 1, I will use CRISPR to knockout ZEB2 in AML cell lines, triggering differentiation and cell death, and use known ZEB2 point mutants to test whether interaction with CtBP-containing corepressor complexes is needed for cell survival and differentiation. I will use ChIP-Seq and RNA-Seq experiments to identify ZEB2 regulated transcripts that drive differentiation. Lastly, because ZEB2 possesses zinc finger domains with features that predict sensitivity to immunomodulatory drug (IMiD)-derivatives, I will use a novel positive selection chemical screening platform to screen diverse drug libraries for small molecule degraders of ZEB2 (Aim 2). This works aims to harness an understanding of the biology of AML to develop novel differentiation and degrader therapies to treat this deadly disease.
Applicant 47
Name: Dr. Joseph Chan
Institution: Memorial Sloan Kettering Cancer Center
Project Title: Early transcriptional, epigenetic, and environmental factors of squamous transformation in lung cancer
General Audience Summary: An emerging mechanism of treatment resistance is lineage plasticity, exemplified by the histological switch from lung adenocarcinoma (LUAD, the most common lung cancer subtype) to squamous lung cancer (LUSC) as an escape from targeted therapies. This process is poorly understood due to dependence on sequencing the bulk tumor, which captures the average signal and is suboptimal for studying tumor diversity (i.e. admixed LUAD/LUSC subpopulations) and the immune microenvironment. Instead, we will use single-cell sequencing and spatial imaging to profile epigenetic and environmental cues driving this process. Early drivers may offer drug targets to intercept plasticity before it progresses, whereas late drivers may offer targets to constrain or reverse plasticity, thereby restoring sensitivity to targeted therapies.
Scientific/Technical Abstract: Tumor plasticity in the form of a lineage switch from lung adenocarcinoma (LUAD) to squamous histology (LUSC) mediates resistance to targeted therapies. A limitation to prior studies is dependence on profiling the bulk tumor, which cannot capture intratumoral diversity or the tumor microenvironment (TME). In contrast, single-cell sequencing and imaging can model gene regulatory networks driving plasticity and the environmental factors that accelerate it. Our work studying an alternative switch from adeno to neuroendocrine (NE) histology showed that LUSC features emerge in pre-transformed LUAD prior to full NE transformation, suggesting that LUSC transformation represents an intermediate step that can be intercepted before plasticity progresses to NE. To study this early window of plasticity, we will apply single-nucleus RNA/ATAC sequencing and Xenium in situ imaging in patient tumors with transformed or admixed LUAD/LUSC histology, with de novo LUSC and LUAD controls, to 1) Identify gene programs driving early, transitional, and late stages of LUSC transformation; 2) Identify early epigenetic changes that initiate histological transformation; and 3) Understand how inflammation affects plasticity and how plasticity in turn molds the immune TME. Candidate drivers of plasticity will be tested in in vitro and in vivo genetic and drug studies, and their use as peripheral biomarkers tested with prospective ctDNA-seq. Early drug targets may intercept plasticity, whereas late targets may constrain or reverse plasticity, thereby abolishing acquired resistance.
Applicant 48
Name: Dr. Joshua Sasine
Institution: Cedars-Sinai Medical Center
Project Title: Development of NK Lineage-Specific Chimeric Antigen Receptor Hematopoietic Stem Cells
General Audience Summary: Recently, a groundbreaking treatment called Chimeric Antigen Receptor (CAR) cell therapy has changed the way we fight certain types of blood cancers, like leukemia. This therapy is made by taking a small portion of a patient’s immune cells (T cells or NK cells) out from their blood and genetically modifying them to recognize cancer cells. We then infuse these back into patients. The therapy is precise and effective, and can cure about a third of patients who receive it. However, for most patients, the cancer returns. Patients are much more likely to be cured if the CAR cells persist in the body for a longer duration of time. Hematopoietic stem cells (HSCs) live in the bone marrow and produce blood cells for life. We plan to engineer these cells with a CAR, then transplant them, aiming to produce a durable output of CAR NK cells.
Scientific/Technical Abstract: Background: Chimeric Antigen Receptor (CAR) cell therapy has ushered in a new era of precision and efficacy in treating B-cell and plasma cell malignancies. Nevertheless, even in diseases where CAR is most potent, more than half of the patients experience rapid disease progression. Several factors contribute to CAR therapy's limited success, one notable factor being the early loss of CAR cells. Patients who achieve durable remission have a substantially higher exposure (area under the curve) to CAR T cells. Natural Killer (NK) cells, equipped with CARs, have demonstrated promising outcomes in clinical trials. In most cases, their response rates match those of CAR T, and the traditional toxicities associated with CAR T therapy are absent or diminished. However, when administered intravenously, NK cells exhibit inadequate in vivo functional persistence, leading to reduced longterm clinical responses. We aim to solve this. Objective/Hypothesis: Hematopoietic stem cells (HSCs) reside within the bone marrow serve as the progenitors for all blood cells. We will engineer adult HSCs to specifically express CARs in their NK cell offspring, upon transplantation. This strategy aims to generate sustained production of HSC-derived CAR NK cells after transplantation.
Applicant 49
Name: Dr. Shun Rhie
Institution: University of Southern California
Project Title: Understanding the mechanisms of prostate cancer genetic risk to tumor immunology
General Audience Summary: Genetic factors play a significant role in prostate cancer, which is the second leading cause of cancer-related deaths in men in the USA. Scientists discovered that variations in our DNA sequences are linked to the risk of developing prostate cancer. However, we have a poor understanding of how these variations contribute to prostate cancer risk. Using advanced molecular biology and bioinformatic analyses, we found that these DNA variations are in enhancers, potentially influencing the immune system. The proposed project will find key molecular factors that will help us better understand prostate cancer etiology and further develop new clinical interventions for prostate cancer patients.
Scientific/Technical Abstract: Prostate cancer (PCa) is the second leading cause of cancer death in men in the USA. Among PCa risk factors, genetic factors largely account for PCa susceptibility. To address this, Genome Wide Association Studies were performed, identifying genetic variants that are associated with disease risk. However, more than 90% of the identified variants are in non-coding regions, making it challenging to know how they contribute to PCa risk. In preliminary studies, we identified PRELs (Prostate cancer Risk genetic variants in Enhancers and involved in Looping), which are PCa risk variants in enhancer regions, potentially regulating immune-related genes. We hypothesize that by characterizing the roles of PRELs in prostate cells, we can identify the molecular mechanisms of genetic variants leading to alterations in the immune system and PCa. In Aim 1, we will determine the impact of allele-specific changes of prostate cancer risk variants on enhancer activity and transcription factor occupancy. In Aim 2, we will identify and characterize the target genes of PCa risk variants involved in tumor immunology. These findings will advance our understanding of PCa etiology, enhance risk assessments, and pave the way for the development of new clinical interventions for PCa patients.
Applicant 50
Name: Dr. Wencai Zhang
Institution: The University of Central Florida Board of Trustees
Project Title: GATM promotes drug tolerance to EGFR inhibition through mitochondrial-nuclear translocation and miR-147b activation in lung cancer
General Audience Summary: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and its survival rate is low. Irstline treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors is used for patients with EGFR mutations, but drug resistance often occurs due to numerous genes that aid cancer cells to survive against EGFR inhibitors, which are still not properly understood. In this study, we will analyze the molecular profiles that cause drug resistance. Our preliminary research indicates that the arginine metabolic pathway contributes to drug resistance, as shown by the whole transcriptomics analysis. We found that GATM, a metabolic enzyme, changes its location from the cytosol to the nucleus, indicating a new function acquired through subcellular translocation. Our research will investigate the functional roles of this nuclear protein in drug resistance and explore how it regulates the expression of other genes and functions in drug resistance. This study could help identify a potential new target to address drug resistance in lung cancer.
Scientific/Technical Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. Targeted therapy against oncogenes such as EGFR has been successfully used in the clinic to treat lung cancer patients. However, the frequent occurrence of drug resistance has limited its long-term efficacy. Research has focused on understanding the molecular changes that occur during late-stage drug resistance, such as secondary EGFR mutations, MET amplification, and oncogenic signaling reactivation. Drug-tolerant persister cells (DTPCs) are the precursor cells that survive after short-term treatment with EGFR TKIs and contribute to developing drug resistance. Therefore, targeting the early phase of drug resistance development can potentially block drug resistance. Studies have characterized the molecular profiles of lung DTPCs against EGFR TKIs, which include activation of pseudohypoxia signaling and dysregulated nucleotide metabolism. Based on previous studies, this proposal aims to further assess the regulation of these signaling pathways. Preliminary data revealed that the mitochondria enzyme GATM gains its function from an enzyme to a transcription factor by nuclear translocation, regulating gene transcription and leading to increased EGFR TKI tolerance. Additionally, MYC and C15orf48 were upregulated in lung cancer cell lines treated with gefitinib. MYC also binds promoter regions of GATM, suggesting that MYC may regulate GATM to acquire drug resistance. Further analysis showed that GATM promotes drug resistance by upregulating miR-147b, the mature microRNA of its host gene C15orf48. This upregulation generates reactive oxygen species and pseudohypoxia response, promoting drug resistance among lung cancer cell lines. The central hypothesis is that aberrantly increased nuclear translocation of GATM promotes drug tolerance to EGFR TKIs through enhanced expression of miR-147b and activated pseudohypoxia response in NSCLC. This proposal aims to use patient-derived organoids and xenografts to determine the role of the GATM-miR-147b signaling axis in developing drug tolerance to EGFR TKIs in NSCLC in Aim 1. Furthermore, the proposal aims to distinguish differential signaling regulated by nuclear and mitochondrial GATM after EGFR TKI treatment in Aim 2. Achieving the goal will provide a new therapeutic approach to targeting drug resistance by inhibiting nuclear translocation of GATM and will increase our understanding of how nucleus-localized GATM regulates noncoding gene expression and function.
Applicant 51
Name: Dr. Lalima Katyayani Madan
Institution: Medical University of South Carolina
Project Title: Using a combinatorial approach to examine aPKC mutations in adenocarcinomas
General Audience Summary: Balanced interactions between multiple proteins contribute to normal cell growth and health. When certain proteins, known as atypical Protein Kinase Cs (aPKCs) turn over talkative with their partner proteins called PAR3/PAR6, cells are misled into proliferating erratically, resulting in cancer. What is the molecular basis of these protein-protein interactions, and can we modify them with medications to prevent or reverse cancers? To achieve this purpose, we are using high-end computational simulations to study movements/dynamics of the aPKC structure to analyze its role in cancer formation, with the goal of using the data for efficient drug development in the future.
Scientific/Technical Abstract: Epithelial cells surround important organs to form permeable barriers that aid in the transfer of nutrients and protect the organs from mechanical stress. The presence of separate apical and basal membranes with unique asymmetric distributions of proteins, lipids, and other macromolecules is a significant property of these cells. This "cell polarization" is accomplished by the coordinated activity of three proteins: Par3, Par6, and atypical Protein Kinase Cs (aPKCs), which comprise the Par-complex signalosome. Cells lose polarity and fail to control their proliferation in adenocarcinomas (such as those of the kidney, pancreas, and lungs). We hypothesize that a change in aPKC kinase activity and/or protein scaffolding with interactors is directly related to loss of cell polarity in adenocarcinomas. We are utilizing an integrated strategy that includes high-end computational structural biology to analyze protein internal dynamics and allostery, as well as cell-based assays to study the role of aPKC in cancer formation. Our combinatorial strategy is a strong tool for discriminating between driver and passenger mutations in aPKC structures, as well as leveraging aPKCs' hitherto unidentified "non-catalytic" or scaffolding capabilities. These investigations will provide fundamental information on aPKCs, which will be useful for therapeutic development in the near future.
Applicant 52
Name: Dr. Felipe Ribeiro
Institution: Washington University in St. Louis
Project Title: Neuroimmune mechanisms of melanoma metastasis to the central nervous system.
General Audience Summary: Metastasis to the central nervous system (CNS) is the main cause of death from melanoma and can be found in up to 90% of the cases at autopsy. The mechanisms by which melanoma cells circumvent CNS immune protection against invasion are unknown. This study will use pre-clinical models of human metastatic melanoma to investigate how CNS immune cells respond to metastatic melanoma and the role of a recently discovered immunomodulatory sensory neurons in supporting tumor cell invasion of the CNS.
Scientific/Technical Abstract: Although significant progress has been made in the treatment of melanoma, it is the cancer type with the highest incidence of metastasis to the CNS. This underscores the existence of pathophysiological events that seem to be particularly exploited by melanoma cells to efficiently evade immune surveillance of the CNS. I described that sensory neurons modulate immune (neutrophils and macrophages) and nonimmune (microfold cells) cells to actively shape immunity at major barrier tissues of the body (skin, gut, and meninges). In a recent study, I’ve shown how meningeal sensory neurons can modulate CNS immunity and demonstrated how some bacterial pathogens can exploit the immunomodulatory activity of these neurons to evade immunity and invade the CNS. Like pathogens, cancer cells also deploy several strategies of immune evasion to spread into the tissues of the body, and their ability to interact with nerves is associated with a higher risk of metastasis. Thus, the neural control of immunity is a promising new area of research that holds great potential to transform the treatment of complex human diseases. This proposal leverages my scientific background in neuroimmunology and cancer neuroscience to investigate the neural components that drive melanoma metastasis.
Applicant 53
Name: Dr. Miller Huang
Institution: Children's Hospital Los Angeles
Project Title: Elucidating the mechanism of chromosome 17q gain-mediated neuroblastoma tumorigenesis
General Audience Summary: Neuroblastoma is one of the most common tumors in kids. The most common genetic change is a gain in a segment of DNA, called chromosomes. In the past, no research could show that chromosome changes cause neuroblastoma since most cancer-related studies used mouse cells which do not have the same genes on their chromosomes. We recently created a new method to study the effects of chromosome changes in a human cell setting. In my proposal, I will use this system to show whether the chromosome changes found in patients can cause a healthy cell to become a neuroblastoma tumor.
Scientific/Technical Abstract: Neuroblastoma is the most common pediatric extracranial solid tumor and the most frequent genetic change is gain of chromosome 17q which also is linked to poor prognosis. Since the genes on mouse and human chromosomes do not align, studying the role of chromosome changes in mouse models was not feasible. My lab recently developed a human stem cell model of neuroblastoma and obtained stem cells that spontaneously gained chromosome 17q. We were able to show that while gain of chromosome 17q itself is insufficient for transformation, it could cooperate with MYCN to accelerate tumorigenesis. We then generated tumor cell lines and performed whole genome CRISPR interference screening and identified potential vulnerabilities that are specific to tumors with gain of chromosome 17q. In my proposal, I seek to find the genes on chromosome 17q that provide the accelerated tumorigenic effect and also identify potential therapeutic targets in neuroblastoma tumors with gain of chromosome 17q. We will validate these findings in the human stem cell model of neuroblastoma and also in neuroblastoma patient tumors. Successful completion of these studies will provide new insight into how chromosome copy number changes influence tumorigenesis and potential therapeutic vulnerabilities.