University Of Tx Md Anderson Can Ctr

NIH Research Projects · FY 2025 · 2025-08

Metastasis to the omentum, an immune cell-rich fatty tissue that drapes from the stomach, causes substantial pain and bowel obstruction. It is difficult to completely resect the omentum and there are no effective strategies that minimize the risk of colonization of preserved omental tissues by occult cancer cells. Omental metastasis commonly occurs in women with ovarian cancer who are 60 years of age or older. Findings that ovarian cancer cells more effectively colonize the omentum of aged mice than young mice strongly implicate that aging increases metastatic competence of the omentum, but the underlying mechanisms are poorly understood. The goal of this study is to identify how aging increases metastatic competence of the omentum and develop strategies that decrease metastatic competence in older females. We recently discovered that a population of innate-like B cells expands in the uninvolved omentum of mice and women with early-stage ovarian cancer, and that these cells exert immunosuppressive properties and potentiate omental metastasis. Furthermore, we identified that innate-like B cells accumulate in the pre-metastatic omentum of young adult mice with ovarian tumors by homing from the peritoneal cavity. In new studies, we discovered that the normal omentum of aged females exhibits a striking expansion of innate-like B cells analogous to the pre-metastatic omentum of young adult females. We therefore hypothesize that heightened metastatic competence of the omentum in aged females stems from age-related increases in innate-like B cells, and that inhibiting homing of innate-like B cells to the omentum decreases metastatic competence in aged females. In this study, we will firstly determine whether heightened metastatic competence of the omentum in aged females stems from increases in innate- like B cells. Secondly, we will determine whether homing of innate-like B cells to the omentum is increased in aged females. Thirdly, we will delineate mechanisms that can suppress homing of innate-like B cells to the omentum in aged females and thereby decrease metastatic competence. These aims will be accomplished by a combination of approaches that utilize genetically modified mice, adoptive cell transfer, clinical specimens of human omentum, single cell analysis, and pharmacologic agents. If successful, our study will yield new mechanistic insights that explain why aging increases metastatic competence of the omentum and valuable insights into strategies for decreasing the risk of omental metastasis by occult ovarian cancer cells in older women.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Orodental sequalae after radiation therapy (RT) for head and neck cancer (HNC) pose a significant problem for survivors, their oncology and dental providers, and the healthcare system. A recent prospective trial using advanced RT techniques and comprehensive pre-therapy dental evaluations found that within 2 years of finishing RT, 18% of patients suffered tooth loss, dose-dependent gingival recession with increased post-radiation caries (PRC) risk was frequently observed, and 6.4% developed bone exposure or osteoradionecrosis (ORN). These orodental toxicities result in diminishing quality of life, especially ORN which is associated with high symptom burden (i.e., dentition and activity limitations) and high financial costs. The combination of a lack of standards for reporting oncologic orodental sequalae, interoperability limitations between electronic medical and dental record systems, and poorly understood biological mechanisms of orodental disease, result in uncoordinated and information-deprived care. Clinically, there exists a knowledge gap on how to conceptualize and report the presence and/or severity of diseases such as ORN which has over 16 published staging systems, or PRC which is often measured using the Post-Radiation-Caries Index or International Caries Detected and Assessment System, both of which underestimate rates of PRC. Moreover, no consensus on assessing or reporting post-RT POD exists. The OPULENCE multi-institutional and multidisciplinary investigative team has started to bridge these unmet needs through published clinical standards for pre- and post-RT assessments and procedures, the development of clinical and image data-driven models for ORN, and contributions to the first publicly available operational ontology for oncology (i.e., for data harmonization and computable knowledge of general cancer care). Furthermore, we have published findings from a small prospective study which showed significant oral microbial shifts and reduced activation of oral neutrophils, changes that correlate with oral inflammation and POD, a known independent risk factor for ORN. Through the OPULENCE Proposal, we aim to open new horizons for early orodental disease diagnosis, toxicity mitigation, and data-driven management by leveraging artificial intelligence/machine learning methods for multi-domain ontology learning with corresponding common data elements highly expressive of the full (clinical, imaging, and biologic) spectrum of orodental disease (Aim 1), facilitating multidimensional, image-based FAIR data generation and application through informatics models of 2D-3D image transformation and NTCP models of PRC and POD (Aim 2), and prospectively identifying deep phenotypes and performing causal analysis on the interplay between biomarkers and post-RT orodental complications (Aim 3). All aims are highly synergistic with NIDCR future research initiative interests including investigations of personalized dental treatment practice prior to cancer therapy, developing risk assessment algorithms for early toxicity detection, monitoring and treating orodental complications, and enabling meaningful oncologic (i.e., medical) and dental care coordination.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT B cells are the master regulators of humoral immune responses, and many autoimmune diseases arise due to the breakdown of self-tolerance in B cells. Understanding the signaling and genetic control of B cell tolerance will lead to the development of new tools for the early detection and treatment of B cell mediated autoimmunity. There is increased evidence on the potential contribution of the E3 ubiquitin ligase gene related to anergy in lymphocyte (GRAIL) in B cell mediated autoimmune diseases; however, to date, GRAIL expression in B cells and its role in B cell mediated immunity and inflammation remains undefined. Our data provides the first evidence of GRAIL expression in both mouse and human B cells, with higher expression particularly in anergic B cells, suggesting that GRAIL may contribute to establishment of B cell tolerance. In fact, GRAIL deficient B cells were hyper-responsive in terms of proliferation upon antigenic stimulation. In addition, aged GRAIL B cell conditional knockout (BcKO) mice developed lupus-like symptoms characterized by high titers of anti-double stranded DNA in the sera, accumulation of T follicular helper and B cells in the lymphoid tissues and spontaneous germinal center formation. Moreover, GRAIL BcKO mice are more susceptible to autoimmune diseases such as lupus and rheumatoid arthritis (RA). Importantly, we detected significantly reduced GRAIL expression in B cells from patients with RA, lupus, and immune checkpoint inhibitor (ICI)-induced arthritis compared to healthy donors, further indicating that GRAIL down-regulation could serve as a marker for onset of B cell mediated autoimmunity. Based on these findings, we hypothesize that regulation of B cell activation and tolerance by GRAIL may be an important checkpoint in censoring and elimination of autoreactive B cells; thus, GRAIL function is crucial to control the onset and development of B-cell mediated autoimmunity. Here in Aim 1, we propose to determine the molecular mechanisms responsible for regulation and function of GRAIL in B cell tolerance by utilizing conditional gene knockdown approaches and in vivo B cell tolerance models. We will identify the exact target(s) of GRAIL, which will determine its function in B cell activation and tolerance. In Aim 2, we will determine the role of GRAIL in antibody-dependent and - independent functions of B cells. The physiological significance of this finding will be assessed in a novel ICI- arthritis model. By utilizing B cell specific GRAIL targeting approach, we will assess whether GRAIL functions in B cells to control ICI-arthritis at the onset and/or progressive stages. In addition, cellular, global transcriptomic, and genome-wide analysis of biospecimens from cancer patients with ICI-arthritis will help to unmask B cell specific role of GRAIL in immune-related adverse event pathogenesis. The proposed research will provide new significant insight into mechanisms underlying B cell tolerance that will lead to development of pharmacological approaches in controlling B cell mediated autoimmunity.

NIH Research Projects · FY 2025 · 2025-08

Abstract Tumor cell of origin is a major determinant of cancer evolution. While the cell of origin of several tumor types has been successfully identified, glioblastoma, a malignant primary brain tumor, remains deprived of such biological information. Although rigorous studies have identified potential candidates among central nervous system cytotypes, a clear consensus of the early tumorigenic steps in glioblastoma has yet to be achieved. Unveiling glioblastoma cell of origin will shed a light on its evolutionary trajectories and, ultimately, better explain disease heterogeneity and poor clinical outcomes. To investigate cell of origin of glioblastoma, I generated multiple technological tools leveraging i) CRISPR/Cas9 genetic engineering, ii) human induced pluripotent stem cells derived cerebral organoids, iii) adeno-associated- and lentiviral gene delivery, iv) genome-tagging dynamic-barcoding. This work laid the foundation of the generation of human pre-clinical model of spontaneous gliomagenesis, thus allowing to trace and characterize early steps of human gliomagenesis. The overarching hypothesis of this research plan is that cell-specific molecular programs are permissive to malignant transformation under the selective pressure of known genetic drivers. To test this hypothesis, the Aim 1 of this work will be focused on characterizing histopathological and transcriptomic alterations following key driver events to provide detailed annotations of early glioblastoma tumorigenesis. To complement Aim 1 and improve our understanding of glioblastoma tumorigenesis, Aim 2 will be focused on developing a reliable platform that will permit to lineage trace glioblastoma cell of origin thanks to a sophisticated CRISPR/Cas9 barcoding technology. Single cell RNA sequencing of these models will generate a computational framework able to identify normal cells susceptible to gliomagenesis and transcriptional programs that lead malignant transformation. Comparative analysis with publicly available single cell RNA sequencing dataset of patient derived glioblastoma, will further advance our knowledge regarding tumor progression. This study will define a comprehensive panoramic of glioblastoma tumorigenesis and clarify its cell of origin, opening new avenues for future clinical therapeutic strategies.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Prostate cancer (PCa) is the second most common cancer-related mortality cause in American males. Although therapies targeting androgen receptors are generally effective in treating advanced PCa, no curative treatments currently exist for castration-resistant prostate cancer (CRPC). Recent research reveals CRPC’s vulnerabilities to oxidative stress due to its unique metabolic reprogramming. This elevated susceptibility creates an environment favorable for a form of cell death called ferroptosis. Ferroptosis is brought about by the intracellular accumulation of toxic lipid hydroperoxides. Hence, ferroptosis induction represents a promising novel therapeutic approach for drug-resistant cancers. Despite increased sensitivity to ferroptosis, CRPC manages to avert this cellular fate. In this proposal, we have identified a key enzyme involved in lipid metabolism, adipose triglyceride lipase (ATGL), that engenders metastatic castration-resistant prostate cancer cells with the ability to resist ferroptosis. Our preliminary data demonstrates that ATGL facilitates prostate cancer growth, migration, and invasion. In CRPC cell lines, ATGL deletion sensitizes prostate cancer cells to ferroptosis, likely through regulating the GPX4-mediated ferroptotic control pathway. However, the exact mechanism linking ferroptosis and ATGL in CRPC is unknown. Moreover, while ferroptosis inducers (FINs) are hopeful candidates for anticancer agents under development, their use for treatment and how to enhance their efficacy remains underexplored in CRPC. Our central hypothesis is that ATGL promotes the resistance of CRPC to ferroptosis inducers in an oxidizable lipid-dependent manner. Therefore, Aim 1, the F99 phase, is designed to (1) identify the underlying mechanisms by which ATGL modulates the regulatory pathways that lead to ferroptosis, and (2) evaluate the efficacy of a combined therapy employing FINs, ATGL inhibitors, and anti-androgens as well as investigate the underlying mechanisms behind the observed synergy between anti-androgens and ferroptosis inducers in the context of ATGL ablation. Dr. Daniel Frigo, Ph.D., in the Department of Cancer Systems Imaging at MD Anderson Cancer Center is the primary sponsor of this F99 phase. Aim 2, the K00 phase, is to demonstrate the role of ATGL’s transacylation activity and its product, fatty acid esters of hydroxy fatty acid (FAHFA) in prostate cancer. Considering the K00 proposal focuses on metabolism and cancer progression, it will be conducted at a laboratory that excels in these fields. The fulfillment of these aims holds promise to deepen our knowledge of cancer biology and guide the development of innovative complementary therapeutic approaches that enhance the effectiveness of anti- androgens, thus improving the clinical outcomes of patients suffering from advanced prostate cancer. The proposal also contains a training plan that details further scientific, technical, and professional training. The plan is formulated to ensure the successful completion of the project and a smooth transition to a future career as an independent investigator.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Research. Lung cancer is the most common malignancy that affects both sexes, with over 238,00 new cases and 127,000 deaths per year. Most lung cancer patients will be treated with radiation as either a primary or adjuvant therapy approach. Despite advancements in lung cancer radiotherapy, radiation-induced lung injury (RILI), typically in the form of radiation pneumonitis (RP), has remained prevalent with incidences of severe RP as high as 40% of patients. RP is a serious treatment-related side effect that can lead to irreversible fibrosis and dyspnea, and greatly reduce patient quality of life. Furthermore, RP limits safely deliverable radiation dose, thereby decreasing treatment efficacy. Therefore, radiotherapy treatment strategies that can reduce or eliminate RP is an unmet clinical need. Functional avoidance radiotherapy is a novel approach to radiation treatments where healthy tissue with the greatest functional capacity is identified by quantitative imaging, and thus spared, when creating a patient-specific treatment. Indeed, hyperpolarized Xenon-129 MRI has shown great promise in identifying lung dysfunction from several pathologies (COPD, asthma, cystic fibrosis, etc.), but this technology has never been implemented to measure longitudinal radiation effects, nor implemented in a functional avoidance radiotherapy approach. Our central hypothesis is that longitudinal Xenon-129 MRI is a predictive biomarker of RP that can be used to create a functional avoidance radiotherapy strategy, which will greatly reduce RP incidence. The long-term objective of this project is to establish Xenon-129 MRI-guided functional avoidance radiotherapy as the optimal treatment strategy for lung cancer radiotherapy by minimizing RILI. Aim 1 determines the effect of baseline lung function, tumor location within the lung, and radiation modality (i.e., whether photon or proton radiotherapy) affects the radiation-response, as quantified by Xenon-129 MRI. Aim 2 establishes Xenon-129 MRI of the lung as a predictive biomarker of RP. Finally, Aim 3 develops a functional avoidance radiotherapy treatment approach and determines the reduction of severe RP as compared to standard-of-care radiotherapy using machine learning. Career Development & Training. Dr. Niedzielski’s long-term career goal is to become an independent investigator in the field of treatment-related pulmonary toxicity prevention using patient-orientated research and advanced quantitative MR imaging. This proposal includes Dr. Niedzielski’s 5-year mentored career development plan, which includes mentoring and collaborations with senior, established NIH investigators in pulmonary medicine, radiation oncology, and MRI engineering. Necessary training in prospective human subject MRI studies, clinical trial design, biostatics, and advanced radiotherapy treatment strategies are detailed in this development plan and build upon Dr. Niedzielski research expertise in toxicity modeling and predictive analytics.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Facial data in medical imaging poses a unique challenge, especially in the treatment of head and neck cancer. While these images are essential for planning and delivering radiation treatments, they also include identifiable features that raise privacy concerns. Techniques to obscure or remove facial features—known as facial de-identification or "defacing"—have been proposed to reduce the risk of patient re-identification. However, these methods often interfere with critical anatomical details needed for precise cancer treatment, particularly in radiotherapy. Currently, there is no clear standard for using these techniques in head and neck cancer imaging, creating uncertainty about the best way to balance privacy with maintaining the usefulness of these images. This administrative supplement will evaluate how different facial de-identification methods affect the quality of medical images used in cancer treatment. We will study how these methods impact important steps in the radiotherapy process, such as identifying tumors and planning treatment. By comparing original images with de-identified ones, we aim to identify which techniques preserve the most critical information while ensuring patient privacy. This work will provide valuable insights into the trade-offs between privacy and the usefulness of medical data, helping researchers and clinicians make more informed decisions. In addition, the project will engage with patients, clinicians, researchers, and other experts to explore their views on sharing medical images containing facial features. Through structured interviews, we will investigate ethical concerns, practical challenges, and potential solutions for responsibly sharing these sensitive datasets. This stakeholder-driven approach will highlight diverse perspectives and provide an evidence base to guide future discussions on privacy and data-sharing practices. This collaborative effort between Baylor College of Medicine and The University of Texas MD Anderson Cancer Center directly aligns with the goals of the NIH and the NIDCR to address ethical and privacy concerns in sharing medical data. By combining technical research with stakeholder engagement, our work will enhance the ability to share high-quality imaging data responsibly. This will not only foster innovation in cancer treatment but also ensure public trust, ultimately benefiting patients and advancing research.

NIH Research Projects · FY 2025 · 2025-07

Project Summary Background: Carriers of germline BRCA 1 and 2 (gBRCA1/2) mutations harbor substantial (60-80%) lifetime risk of breast cancer. Current strategies for management of this high risk population are limited to either bilateral mastectomy to reduce risk or breast MRI surveillance for early detection of cancer. Both strategies are associated with significant risks and morbidities. Therefore, there is a clear need to develop effective, low toxicity approaches as alternatives to current standard of care. Advances in genomics and bioinformatics have opened the door for novel mRNA and peptide vaccines for treatment of cancer. These advances offer as yet untapped opportunities for prevention of breast cancer, including gBRCA 1/2 related disease. However, to realize these opportunities, it is first necessary to identify the antigenic repertoire that arises during tumorigenesis that can be harnessed to develop preventive vaccines. Our group has made the observation that breast tumors, including those from BRCA 1/2 mutation carriers, as well as risk breast tissue harbors significant numbers of chimeric mRNA which give rise to de novo, immunogenic neoantigens that we believe represent an ideal opportunity as vaccine targets. Objective/Hypothesis: We hypothesize that an approach of genomic characterization of preneoplastic breast tissue from gBRCA1/2 carriers to identify novel fusion proteins arising from chimeric mRNAs, coupled with bioinformatics prediction of immunogenic peptides, will provide a robust opportunity for developing vaccines for prevention of breast cancer in this high risk population. We will test our hypothesis through the following aims: UG3 phase Specific Aim 1: Using our established pipeline, we will identify and validate MHC Class I immunogenic peptides generated from chimeric mRNA transcripts as potential vaccines for prevention of gBRCA 1 and gBRCA 2 related breast cancer. UH3 phase Specific Aim 2: Using a transgenic mouse model of BRCA 1 breast cancer, we will provide proof of principle that the framework proposed in aim 1 will yield an effective chimeric mRNA derived vaccine for prevention of breast cancer. UH3 phase Specific Aim 3: we will delineate the mechanism of immuno-prevention by a multiantigen mRNA vaccine in BRCA1 mouse model. Impact This application provides a paradigm shift in breast cancer prevention by bringing together genomics, bioinformatics and immunology to create an innovative, integrated, multi-disciplinary framework that will address many of the current barriers to primary prevention of hereditary breast cancers and provide a path to developing off-the shelf cancer immuno- prevention vaccine that would be applicable to most women at risk for germline BRCA1/2 driven breast cancer. If effective, this framework could readily be extended to hereditary cancers associated with additional high penetrance germline mutations. Given this broad applicability, our proposed strategy is positioned to make significant impact toward the overall goal of reducing the incidence of breast cancer.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Gastric cancer is the fourth most common cause of cancer deaths worldwide, with five-year survival rates of slightly over 20%. More than 90% of gastric cancer cases belong to gastric adenocarcinoma (GAC), which can be further divided into intestinal-type gastric cancer (IGC) and diffuse-type gastric adenocarcinoma (DGAC). While the overall incidence of GC has decreased, the incidence rate of DGAC is increasing. Unlike IGC, DGAC is more commonly observed in younger patients, females, and the Hispanic populations. DGAC is aggressive and tends to be detected at later stages, resulting in poor prognosis and limited treatment options. DGAC is resistant to systemic therapy, and the progress toward targeted therapy for DGAC treatment is relatively slower. Additionally, biomarker-guided therapeutic options are limited. Therefore, the development of a new therapy is crucial. The proposed study aims to unravel the mechanisms of DGAC tumorigenesis and apply that knowledge to laying a foundation for DGAC therapy development. To address this, we established a model system that recapitulates human DGAC tumorigenesis using genetically engineered gastric organoids and transplantation approaches. Single-cell transcriptomics helped us delineate the cell dynamics, cells of origin, and cell plasticity of DGAC. Our findings led us to identify potential drugs that target the root cells driving the neoplastic cell lineage of DGAC. Based on the preliminary results, we hypothesize that drugs identified by single-cell transcriptomics inhibit neoplastic cell lineages and suppress E-cadherin-negative DGAC tumorigenesis, which will be tested by pursuing the following aim: To determine the impact of drug candidates on DGAC stemness, tumorigenesis, and first-line treatment. Completing the proposed study will lay a novel foundation for DGAC therapy development by determining whether targeting specific cell clusters inhibits E-cadherin-negative DGAC tumorigenesis.

NIH Research Projects · FY 2025 · 2025-07

Project summary/abstract African American (AA) men are at higher risk of prostate cancer diagnosis and metastasis, and men of all races and ethnicities with low socioeconomic status are also at risk of adverse prostate cancer outcomes. There is great interest in determining noninvasive interventions, such as dietary change, that can slow or stop disease progression, especially because prostate cancer treatment can negatively affect men’s quality of life and because many men with localized disease will ultimately die of causes other than cancer (most commonly cardiovascular disease). Such interventions are especially desirable for men on active surveillance (AS), a treatment strategy whereby a low-risk tumor is actively monitored for signs of progression, at which point patients may undergo radical treatment. Unfortunately, while studies suggest that lifestyle changes may modify factors associated with prostate cancer progression, no dietary intervention has been shown to slow prostate cancer progression rates, and none have been developed specifically for underrepresented minority men with prostate cancer, who are at increased risk of adverse outcomes. Our group has shown that a Mediterranean- type diet may be associated with decreased risk of progression over time in men on AS. As shown in the landmark PREDIMED study, a Mediterranean diet protects against major cardiovascular events, likely due to its known lipid-lowering and anti-inflammatory effects. It also has a direct effect on the gut microbiome, which is increasingly recognized for its role in metabolism and cancer therapy. In this proposal, we aim to define dietary patterns and barriers to dietary change among underrepresented minority men with localized prostate cancer. We will also adapt the PREDIMED diet intervention for this group, allowing us to then determine the feasibility of enrolling to and performing the intervention in a medically underserved population. We will first form focus groups of AA and Hispanic men diagnosed with prostate cancer (and their significant others) and perform qualitative analyses to determine dietary habits and cultural factors related to diet. In parallel, we will complete adaptation of the PREDIMED diet intervention, after which we will perform a pilot feasibility study of the adapted dietary intervention among 25 men recently diagnosed with localized prostate cancer at a large safety net hospital. We will also assess noninvasive biomarkers, including a lipid-based signature described by our group and gut microbiome composition, for their association with dietary change in the intervention study population. This will allow identification of candidate markers of prostate cancer response to dietary intervention for use in future clinical trials. This award will allow the PI to gain experience in designing and administering a behavioral intervention while taking part in a structured learning plan consisting of mentorship and formalized coursework in health disparities research and nutritional interventions. This training, coupled with experience gained in this award, will provide the foundation needed for an independently funded career as a surgeon-scientist dedicated to improving the lives of medically underserved men with prostate cancer.

NIH Research Projects · FY 2025 · 2025-07

Project Summary Lung cancer is a devastating disease that remains the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. We recently demonstrated that Smarca4 acts as a bona fide tumor suppressor in mice and cooperates with p53 loss and Kras activation. Importantly, SMARCA4 mutant cancer cells have heightened sensitivity to inhibition of oxidative phosphorylation (OXPHOS) by a novel small molecule, IACS-10759. Mechanistically, we showed that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a therapeutically relevant vulnerability. Taking these observations together, we hypothesize that OXPHOS inhibition using IACS-10759 is an attractive therapeutic strategy for lung cancers with mutations in the SWI/SNF complex. The major objectives of the proposed study are to discover the mechanistic basis of the metabolic rewiring in SWI/SNF mutants and provide preclinical evidence to guide future clinical study of IACS-10759 in patients with SWI/SNF mutant lung cancer. Due to the unique microenvironment of lung cancer including high local oxygen tension, it is imperative to study therapeutic agents targeting metabolism orthotopically. Hence, we will test efficacy of IACS-10759 in GEM models of lung cancer. Further, PDX models have emerged as powerful tools to help guide treatment strategies. Thus, we propose to determine the potential of OXPHOS inhibition in various SWI/SNF mutant PDX model systems. While our preliminary data indicates that IACS-10759 treatment leads to tumor growth inhibition, synergistic combination strategies are expected to be even superior in efficacy. Thus, we propose to identify optimal combination agents that synergize with IACS-10759 by using a chemo-genetic screen. Here, we will use CRISPR-Cas9 and a custom designed library of guide RNAs against genes targeted by FDA approved drugs (FDAome). We will validate the results of the screen by performing one-on-one drug combination studies in vivo. Finally, our preliminary data suggests that SMARCA2 is required for expression of PGC1α, a master transcriptional regulator of mitochondrial biogenesis and OXPHOS, in SMARCA4 mutant cells. We know from our published work that PGC1α is essential in SMARCA4 deficient cells. Thus we hypothesize that SMARCA2 is a survival factor and a major driver of metabolic rewiring in SMARCA4 deficient cells in a PGC1α dependent manner. In conclusion, our study is expected to provide mechanistic insight into the metabolic dysregulation of SWI/SNF mutant lung cancers and lay the foundation for future clinical development of the OXPHOS inhibitors as therapeutics.

NIH Research Projects · FY 2026 · 2025-07

PROJECT SUMMARY Current treatments of diabetic kidney disease (DKD) mainly focus on managing the symptoms of diabetes and do not address the root causes of DKD. Among causal mechanisms associated with the progression of DKD, there is growing recognition of the central role of mitochondrial dysfunction. Importantly, various aspects of mitochondrial function in kidney cells are known to be impaired in experimental models and in individuals with DKD, including enhanced generation of reactive oxygen species (ROS), substantial alterations in mitochondrial dynamics and structure, and mitochondrial electron transport chain dysfunction. Dysregulated mitochondrial electron transport chain (ETC) has recently emerged as a leading cause of mitochondrial dysfunction in DKD, contributing to the progression of DKD and other micro/macrovascular complications of diabetes. However, the nature or ETC dysfunction in the development of DKD remains unknown. This proposal is based on our recent observations (Mise K. et al. Nature Commu 2024), indicating that: (1) the expression of Ndufs4 (NADH: ubiquinone oxidoreductase iron-sulfur protein 4), a subunit of the complex I of the ETC, is consistently reduced in kidney podocytes of diabetic mice; (2) conditional overexpression of Ndufs4 in the podocytes of diabetic mice (Ndufs4podTg) restored ETC function and improved mitochondrial dynamics and structure in podocytes; and (3) diabetic mice with Ndufs4podTg exhibit significant improvement in albuminuria and kidney morphology compared to control DKD mice. Overall, these discoveries highlight the role of ETC remodeling under diabetic conditions. However, several key questions remain to be carefully addressed, including, a) is mitochondrial ETC regulated in DKD? and if so, how? b) can we unbiasedly identify novel regulators of ETC remodeling in DKD? and c) what are the molecular mechanisms and physiological consequences of altered ETC regulators in DKD? In this application, we propose to address these questions by designing an unbiased genome-wide single-cell CRISPR (clustered regularly interspaced short palindromic repeats) platform to identify and validate regulatory genes that affect mitochondrial ETC fitness in DKD. As a proof of principle, we recently conducted a pooled genome-wide CRISPR interference (CRISPRi) screen using a mouse sgRNA library and a mitochondrial ROS sensitive reporter (mito-roGFP2) in Ndufs4 deficient (Ndufs4+/-) vs. Ndufs4+/+ wild type cultured podocytes. We identified a subset of genes that are involved in mROS generation in a Ndufs4-dependent manner in podocytes. We now propose under three well- defined Specific Aims to identify and dissect the molecular mechanisms of action of putative regulators of Ndufs4- mediated ETC dysfunction. We believe that the successful completion of this application will not only fill the knowledge gap on regulators of ETC but will also provide foundational insights into the pathogenesis of DKD. Developing novel strategies based on restoring ETC activity in DKD could be a promising approach toward correcting kidney cells energetics which represents a paradigm shift in the management of DKD patients.

NIH Research Projects · FY 2026 · 2025-06

Current therapeutic interventions remain largely palliative in patients with bone metastases. For instance, treatment with zoledronic acid or denosumab can inhibit bone resorption, reduce the risk of skeletal-related events, and alleviate bone pain; however, their clinical use for bone metastasis is insufficient. Our research addresses the urgent need to transform bone metastasis treatment by exploring a new driver and therapeutic vulnerability of bone metastasis. Leveraging an in vivo positive selection system based on CRISPR activation, we conducted a forward genetics screen that led to the discovery of a bone metastasis driver, acyl-CoA binding protein (ACBP), whose role in cancer metastasis has not been reported previously. In preliminary studies, overexpression of wild-type ACBP, but not the acyl-CoA-binding deficient mutant, in non-metastatic and weakly metastatic cancer cells stimulated fatty acid oxidation (FAO) and bone metastasis. Conversely, knockout of ACBP in highly bone-metastatic breast cancer cells abrogated metastatic bone colonization. Moreover, overexpression of ACBP in cancer cells boosted the production of ATP and NADPH, reduced levels of reactive oxygen species, and inhibited lipid peroxidation and ferroptotic cell death (ferroptosis). Notably, we found a significant correlation of ACBP expression with metabolic signaling, bone metastases, and poor clinical outcomes. Building upon our preliminary findings, we will study the function and mechanism of action of ACBP in breast cancer bone metastasis, as well as its therapeutic potential. Specifically, we will test the hypothesis that ACBP promotes bone metastasis by regulating lipid metabolism – stimulating FAO while protecting against lipid peroxidation and ferroptosis. In addition to tumor cell-autonomous effects, we will investigate ACBP’s role in intercellular communication, such as whether bone marrow adipocytes transfer fatty acids to ACBP-expressing breast cancer cells and whether ACBP propagates FAO activation between tumor cells. Moreover, we will examine the impact of ACBP on the tumor microenvironment at primary and bone-metastatic sites, focusing on the recruitment of specific populations of immune cells and stromal cells. Further, we will explore whether blocking FAO or neutralizing ACBP through targeted therapeutic agents can inhibit breast cancer bone metastasis. If successful, this project could illuminate new pathways through which tumor cells adapt to and thrive in the bone, providing insights that may guide the development of novel therapies targeting bone metastasis in breast cancer and other cancers.

NIH Research Projects · FY 2025 · 2025-06

PROJECT ABSTRACT Interleukin-13 receptor alpha-2 (IL13Rα2) is expressed with high frequency and specificity on some of the most aggressive and deadly cancers such as glioblastoma (GBM), basal-like triple-negative breast cancer, and metastatic colorectal cancer. GBM is a highly aggressive primary brain tumor with dismal prognosis; its infiltrative nature makes it difficult to detect and eliminate disseminated cells, and their high mutagenic potential increases resistance to conventional treatment regimens. In GBM, IL13Rα2 is expressed on bulk and glioma stem cells, which are generally resistant to cytotoxic therapies, leading to treatment failure and tumor recurrence. Radioimmunotherapy (RIT) has the potential to address this critical problem, as it offers specific targeting of cytotoxic radioisotopes while sparing normal tissues, thus enabling delivery of tumoricidal radiation doses to multiple dispersed sites. IL13Rα2 is a cell surface receptor expressed on highly malignant tumors with negligible expression in normal tissues, which limits potential side effects from off-site targeting and makes it an ideal target for RIT. Radiation from RIT induces cell kill when DNA is damaged beyond the capacity of the cell to repair. Beta (β) particles have a long range of deposition in tissues, usually many cell diameters. This is advantageous for killing tumors, which exhibit heterogenous antigen expression. 177Lu is a beta-emitting isotope currently used in commercial products, but 161Tb has demonstrated superior anti-tumor efficacy compared to 177Lu in preclinical and early clinical investigations since its decay results in the release of β-emitter as well as Auger-electrons, which may lead to higher tumor-absorbed doses than with 177Lu. Targeted α-therapy with 225Ac (α-emitter) is ideal for localized cell kill due to its limited range in tissue. It is effective even in hypoxic tumor regions. So far, however, no radiolabeled agent targeting IL13Rα2-positive malignancies is clinically available. To overcome this limitation, we have isolated human monoclonal antibodies that specifically bind IL13Rα2 with picomolar affinity. The primary objectives are to establish a radiotheranostic approach for IL13Rα2-expressing GBM. We will perform in vitro assays including saturation binding assays with the radiolabelled antibodies to validate target specificity, assess binding kinetics, and to determine stability, cell-level radiation toxicity, and dosimetry. Furthermore, we will develop a radiotheranostic approach in orthotopic xenograft mouse models of GBM (including PDX model) and compare RIT with 177Lu vs. 161Tb vs. 225Ac. Systemic and locoregional delivery will be explored. Developing an RIT approach using a human antibody that binds to IL13Rα2-expressing cancer cells with high affinity and specificity will significantly expand the therapeutic potential for the treatment of GBM and other hard-to-treat malignancies, such as basal-like breast and colorectal cancers. MSK’s facilities and team with expertise in the successful development of novel radiopharmaceuticals, clinical translation, and obtaining FDA approval will ensure the feasibility and applicability of this technology.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Focal amplifications and structural variants arise from ongoing processes of genomic instability, a hallmark of cancer. They often affect prevalent cancer driver genes and were the first classes of clinically actionable genomic alterations for targeted therapies. Despite their prevalence and clinical significance, their place in cancers' recur- rent evolutionary patterns has been relatively underexamined compared to point mutations (SNVs) and simple copy number alterations (CNAs). The temporal order, or relative `timing', of SNVs and low-level CNAs (< 10 copies) in tumor evolution has been characterized in thousands of tumors across dozens of tumor types. This has provided insight into their role in tumorigenesis and progression and revealed opportunities for early cancer screening. Moreover, these evolutionary reconstructions may inform efforts in precision medicine by revealing recurrent drivers that are often acquired early or late in cancer progression, upon treatment, at recurrence, and in metastases. Recent work from our lab has significantly improved temporal resolution for evolutionary recon- structions of low-level CNAs during clonal evolution. Here, we will build on this work and develop evolutionary reconstruction approaches bespoke to focal amplifications and structural variants and map the evolutionary tra- jectories of complex genome rearrangements in pan-cancer datasets and two novel cohorts of rare tumors in which these alterations play a significant role. In Aim 1, we will develop two separate, complementary approaches for evolutionary reconstruction of amplifications and complex rearrangements. Aim 1A will produce Amplicon Gain And Velocity Estimation (AGAVE) which will time when, and how quickly amplifications occurred during clonal evolution. Aim 1B will produce Reconstruction Of Structural Evolution (ROSE) which will assemble partially ordered chronologies of structural variants formed during clonal evolution. We hypothesize that the evolution- ary patterns of amplifications and rearrangements provide insight into their causes and consequences. To investigate this hypothesis, we will use these methods, and others, to map trajectories of structural evolution in thousands of primary and metastatic tumors across dozens of tumor types. In Aim 2A, we will perform a pan- cancer analysis of structural evolution in 8,000+ primary and metastatic tumors from the TCGA, ICGC, and Hartwig cohorts. In Aim 2B, we will investigate the role of potential structural evolution in the tumorigenesis, progression, and differential survival of spontaneous and radiation-associated undifferentiated pleomorphic sar- coma. Lastly, in Aim 2C, we will reconstruct the evolution of rearrangements and amplifications in small cell lung cancer metastases sampled at autopsy, identifying potential roles for these alterations in metastasis and thera- peutic resistance in this highly lethal, frequently metastatic cancer. These studies will produce the most comprehensive portraits of tumor evolution to date, address a long-standing absence of complex ge- nome rearrangements from models of tumor evolution, and elevate our understanding of their roles in tumorigenesis, progression, and metastasis.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Solid tumors can shape their microenvironments to maximize their growth and metastatic potential. The formation of new nerve fibers within and around tumors can alter tumor behavior, and higher densities of nerve fibers in the tumor microenvironment are associated with poor clinical outcomes in patients with oral, prostate, breast, gastric, pancreatic and other types of cancer . Preclinical and pathological studies have described neoneurogenesis, the process by which cancer cells induce the growth of nerves into tumors, as analogous to neoangiogenesis, in which cancer cells release factors that elicit the growth of blood vessels into the tumor. However, the exact mechanisms that drive nerves to infiltrate tumors and support their growth and progression is unknown. Preliminary research shows that cancer cells `communicate' with neurons The hypothesis of this study is that axonal sprouting and autonomic reprogramming of existing nerves occur as a result of orchestrated miRNA shuttling from cancer cells to neurons and via activation of the transcriptional programs that establish neuronal identity and that infiltration of tumors by autonomic neonerves enables tumor progression. The neonerve's phenotype includes through shuttling of p53-dependent RNA species that further induce tumor innervation. transformation into a sprouting cell able to infiltrate and interact with other cell types, the release of adrenergic neuroactive molecules, and the development of neurogenic inflammation. Each of these acquired capabilities may promote tumor progression and resistance to therapy. The proposed research is innovative because it will capitalize on new concepts in cancer biology and advanced model systems to yield insights into the mechanisms of tumor progression and identify new targets for cancer therapy. This cross-disciplinary proposal will combine expertise from oncology, neurodevelopment, cell biology, neurobiology, cancer genetics, pathology, and biostatistics to pursue three specific aims: (1) Delineate the signaling events that occur between cancer cells and neurons during tumorigenesis, using pharmacologic and genetic approaches to understand how cancer cells cause normally quiescent neurons to reprogram and continually sprout to sustain neoplastic growth. (2) Elucidate the drivers of tumor-associated neuronal reprogramming. By using human-derived sensory neurons, we will determine how the normal nerve response to signals from cancer cells supports cancer progression. (3) Characterize sensory nerve reprogramming and its role in oral cancer progression. Using a genetically engineered syngeneic mouse model, we will elucidate the neural-tumor interactions that lead to neurogenic inflammation and promote oral cancer progression. Our long-term goal is to elucidate the reciprocal nerve-cancer signals that drive cancer progression to identify novel targets for therapy. Once the signals that induce tumor innervation are known, therapeutic approaches to target this critical component of tumor biology can be developed to improve survival, treatment responses, and patients' quality of life.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY Despite dozens of agents targeting the myeloid checkpoint CD47 entering clinical trials, their variable tumor- type impact has spurred a search for complementary biologics to augment tumor inflammation. Antitumor immune responses in antigen-presenting cells (APCs) are catalyzed by the engulfment of tumor cells and the recognition of tumor-derived DNA by cytoplasmic nucleic acid sensors. Nevertheless, these immunogenic processes are hindered by phagocytic checkpoints and inefficient translocation of nucleic acids from phagolysosomes into the cytosol. Cytoplasmic extrachromosomal DNA (ecDNA) functions as a potent innate immunostimulant. However, no therapeutic strategies specifically target phagolysosomal release of ecDNA or other tumor-derived contents within professional APCs. To overcome these challenges, we recently engineered an antibody-drug conjugate (ADC) that targets the “don’t eat me” signal CD47 linked to the bacterial toxin listeriolysin O from the intracellular bacterium Listeria monocytogenes via a cleavable linker (CD47-LLO). CD47-LLO promotes the phagocytosis of cancer cells followed by the activation of LLO which disrupts phagolysosomal membranes and allows for cytosolic escape of tumor-derived contents in APCs. The current proposal explores the use of CD47-LLO to promote antitumor immune responses against recalcitrant tumor types that produce high levels of ecDNA. Aim 1 of the proposal will mechanistically examine how ecDNA detection in APCs triggers potent and broad antitumor signaling pathways. For Aim 2, we will examine how phagolysosomal release of ecDNA stimulates both innate and adaptive immune responses. Finally, for Aim 3, we will evaluate the antitumor effect of CD47-LLO in combination with frontline therapies in animals bearing gliomas or colorectal cancers with high ecDNA expression. If successful, this proposal will support bench-to- bedside translation of an immunostimulatory ADC with potential to destroy diverse cancers that harness ecDNA for survival. This research will be performed by Dr. Benjamin Schrank, a radiation oncologist at the University of Texas MD Anderson Cancer Center. Dr. Schrank will be advised by a multidisciplinary mentoring team consisting of physician-scientists, oncologists, immunologists, and tumor biologists. His primary mentor, Dr. Wen Jiang, is a recognized expert in cancer nanomedicine; his co-mentor, Dr. Betty Kim is known for her neurosurgical and preclinical work on glioblastoma. They will be joined by Dr. Linghua Wang, a pioneer in tumor immunology and spatial transcriptomics; Dr. Jian Hu, a leader in cancer neuroscience; and Dr. Michael Curran, an internationally recognized cancer immunotherapy expert. MD Anderson provides an outstanding environment for Dr. Schrank’s career development. Resources and equipment critical to the proposed research are readily available on campus. Together, the proposed research, training, and career development plan will provide Dr. Schrank with the expertise needed to achieve independence and apply for his first R01.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Targeting the molecular abnormalities driving malignant glioma has proven challenging, due in large part to the inherent heterogeneity and complexity of the fully transformed cancer state. An improved understanding of the molecular and cellular events preceding glioma formation has the potential to elucidate innovative and practice- altering patient management paradigms. This proposal seeks to clarify this understudied research area, focusing on the concept of preneoplastic priming in glioma cell-of-origin pools. Our studies focus on glioma-associated risk SNPs (GASNPs), which have been shown in epidemiological studies to increase the likelihood of glioma acquisition but not invariably cause disease. GASNPs tend to localize to enhancer domains in proximity to established cancer-associated genes (e.g., TP53), suggesting that their presence fundamentally alters epigenomic landscapes and phenotypically relevant gene expression. We recently demonstrated in human induced pluripotent stem cell (iPSC)-derived isogenic organoids that two GASNPs, rs7572263 and rs78378222, impair normal neuronal differentiation, arresting cells in the neural progenitor stage. Intriguingly, this finding echoes earlier work by our group, implicating partially differentiated neural progenitors as cells of origin for major glioma subclasses. Accordingly, we hypothesize that these GASNPs fundamentally alter epigenomic landscapes and transcriptional profiles in developmentally relevant contexts, expanding and neoplastically priming distinct precursor cell pools. In this proposal, we will leverage single cell and bulk profiling approaches in recently optimized iPSC and knock-in mouse reagents to interrogate the epigenetic and transcriptional mechanisms by which rs7572263 and rs78378222 dysregulate neurodevelopmental trajectories and promote gliomagenesis. If successful, our work will lay the foundation for more comprehensive studies moving forward, conducted by our team as well as other groups, and reveal tangible opportunities for improved treatment and management strategies for an intractable and deadly disease.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY Lung adenocarcinoma (LUAD) is the most common type of non-small cell lung cancer (NSCLC) and is, for the most part, causally related to tobacco exposure. Despite recent advances in treatment (e.g., immunotherapy), LUAD patients still often display poor prognosis in part due to inferior therapeutic responses and late diagnosis. There is a pressing need for effective strategies to prevent or treat early-stage LUAD in high-risk individuals such as lifetime smokers. Accumulating evidence has shown that microorganisms in the gut can shape overall immunity and influence states of health and disease, including cancer at the systemic level. Yet, we still do not fully understand the role of the gut and host microbiome in development of LUAD, the most common type of malignancy outside the gastrointestinal tract. We previously showed that gut microbiome changes are strongly associated with development of LUAD in a human-relevant, tobacco-associated mouse model (Gprc5a-/-; G). On top of this, knockout of Lcn2, an antimicrobial protein, in these mice (Gprc5a-/-/Lcn2-/-; GL) reduced microbial diversity while enhancing inflammation, including expression of various pro-inflammatory cytokines such as IL- 6, and lung tumor development. These earlier and preliminary findings motivate my hypothesis that gut microbial dysbiosis (such as that incurred by Lcn2 loss) can stimulate a systemic inflammatory cascade conducive to tumor growth via an IL-6-dependent pathway. I will address this hypothesis through two aims. Aim 1 will determine how gut dysbiosis impacts immunomodulation and inflammation during LUAD development. Using genetic deletion (global and immune-subset specific) and pharmacological inhibition strategies, I will dissect the role of the IL- 6/STAT3 pathway downstream of gut microbiome dysbiosis in LUAD pathogenesis and immune responses. Aim 2 will interrogate the preventive and early therapeutic roles of specific bacterial taxa, alone or in combination with anti-inflammatory agents, in mitigating LUAD pathogenesis. Specifically, I will examine the effects of Limosilactobacillus reuteri treatment in tobacco carcinogen-exposed animals on LUAD pathogenesis, including in combination with strategies targeting IL-6/STAT3 signaling. Leveraging human-relevant mouse models and cutting-edge immune profiling techniques, I aim to unravel the intricate interplay between gut dysbiosis, inflammation, and LUAD development, paving the way for innovative prevention and early intervention strategies. This research endeavor not only seeks to deepen our understanding of host mechanisms governing LUAD progression but also pave way for development of novel avenues for prevention and treatment, potentially incorporating probiotic interventions. By targeting high-risk individuals, such as smokers, with tailored approaches, we aspire to alleviate the burden of LUAD and improve outcomes for affected individuals.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Glioblastoma (GBM), the most common and deadly form of primary brain tumor in adults, is defined by high molecular heterogeneity that renders tumors highly refractory to therapy. Glioblastoma stem cells (GSCs) are a key population within this heterogeneity, harboring proliferative and self-renewal capacities to promote growth, invasion, and resistance. Deciphering key mechanisms of GSC maintenance during gliomagenesis will inform the development of novel GBM therapeutic strategies. Our lab has characterized Quaking (Qki), which is lost in 50-60% of GBM cases, as an important GBM tumor suppressor. Deletion of Qki in a pre-malignant genetic mouse model induces the formation of GBM tumors. Mechanistically, Qki functions as a transcriptional co-activator that regulates both the protein and lipid compartments of the endolysosomal system. Notably, Qki loss compromises endolysosomal degradation and enriches self-renewal receptors at the cell surface, enabling GSCs to maintain stemness and expand outside their niche. It remains to be explored whether other mechanisms of Qki dysregulation govern the maintenance of GSCs in cases where Qki remains intact. Cancer genomic data reveals recurrent mutations to specific Qki arginine residues that implicate the dysregulation of arginine methylation, which is catalyzed by protein arginine methyltransferases (PRMTs). Previous studies reveal that Qki interacts with a PRMT called co-activator associated arginine methyltransferase 1 (CARM1), and our preliminary data shows that Qki is selectively methylated by CARM1. In this proposal, I intend to elucidate the role of CARM1- mediated methylation of Qki in the maintenance of GSCs during gliomagenesis. By establishing stable Qki methylation mutant cell lines and generating a novel genetic mouse model with the brain-specific deletion of CARM1 on a pre-malignant background, I will employ a range of molecular, cellular, bioinformatic, and lipidomic experimental approaches with aims to 1) characterize the molecular function of CARM1-mediated methylation of Qki and 2) determine the impact of Qki arginine methylation on endolysosomal degradation and gliomagenesis. Successful completion of this proposal will provide critical insight into novel pathomechanisms underlying GBM and illuminate new GBM therapeutic strategies that utilize Qki methylation status as a determinant for patient stratification. Moreover, this proposal will provide me, the Principal Investigator, with rigorous technical training and valuable experiences tailored for my development as an innovative researcher. The lab of my sponsor Dr. Jian Hu at MD Anderson Cancer Center represents an exceptional environment for me to complete my project. Additionally, my co-sponsor Dr. Mark Bedford provides critical mentoring, scientific expertise, and technical support to enrich my project and education. With my graduate program, I will receive extensive training in the foundations and applications of cancer biology and varied opportunities to prepare me for my career goal of becoming an independent academic researcher.

NIH Research Projects · FY 2026 · 2025-04

Project Summary Small cell lung cancer (SCLC) is a highly aggressive, neuroendocrine malignancy that follows predictable and dispiriting clinical course. Initially, SCLC patients are uniformly treated with combination chemo-immunotherapy and, for most patients, this approach initially appears successful with dramatic improvement in clinical symptoms and tumor burden. However, just as rapidly as the tumor recedes, it invariably recurs and, upon recurrence, exhibits more molecularly heterogeneous and drug-resistant biology. This narrowly missed opportunity in which SCLC is nearly vanquished only to re-emerge even stronger highlights the urgent, unmet need to identify and target those drug tolerant persister cells (DTPCs) responsible for this malignant sleight of hand. This need is explicitly articulated by the National Cancer Institute’s Scientific Framework for Small Cell Lung Cancer as one of five initiatives within the Recalcitrant Cancer Act - “investigate the mechanisms underlying both the high initial rate of response to primary SCLC therapy and the rapid emergence of drug and radiation resistance following completion of treatment”. To address this need, we have assembled an unparalleled repository of SCLC patient samples and patient-derived models from all relevant clinical timepoints, as well as a multi-disciplinary team with scientific, clinical, translational, and computational expertise in SCLC. Our preliminary data in SCLC models validate not only the existence of these long-hypothesized DTPCs, but also the feasibility of their procurement for molecular and therapeutic analyses. Further, we have demonstrated the relapsed SCLC state is enriched for, though not solely composed of, putative DTPCs with unique therapeutic vulnerabilities. Based on these data, we hypothesize that we can technically enrich for and select DTPCs from SCLC genetically-engineered and patient- derived models, as well as patient samples, and that their cell surface proteome represents an actionable vulnerability for their elimination. To address these hypotheses, we propose the following Aims: in Aim 1, we will collect DTPCs and molecularly characterize DTPCs in SCLC models treated with standard platinum-based chemotherapy to then track their emergence and trajectory in models and patient samples. In Aim 2, we will characterize the ability of the newest class of just-approved SCLC agents – a bi-specific T-cell engager (BiTE) against Delta-like ligand 3 (DLL3) – to shape, or even eliminate, the post-platinum DTPC population. Lastly, in Aim 3, we will develop preclinical antibody-based therapeutics, like antibody-drug conjugates (ADCs) or chimeric antigen receptor (CAR) T-cells that specifically target surface proteins enriched in those DTPCs that survive both platinum-based chemotherapy and DLL3 BiTEs. Together, these aims will comprehensively characterize and validate the DTPC landscape following state-of-the-art SCLC treatments and offer clear candidates for their elimination in future clinical trials.

NIH Research Projects · FY 2026 · 2025-04

Project Summary: BAF (BRG1/BRM-associated factor) complexes are ATP dependent chromatin-remodeling complexes which contain mutually exclusive, core ATPases, BRG1 (SMARCA4) and BRM (SMARCA2). The canonical (c) BAF complex subunits bind and allow transcription factors (TFs) and co-factors to gain access to the chromatin and modulate lineage-specific gene transcription in hematopoiesis. BRG1 is a dependency in AML cells, including those with MLL rearrangement (MLLr) or mutant (mt) NPM1, representing 40% of adult AML. Although Menin inhibitors (MIs) induce clinical remissions, most patients of AML with MLLr or mtNPM1 relapse with MI-resistant AML, based on adaptive, dysregulated gene-expressions or hotspot mutations in Menin, abrogating MI activity in AML cells. This creates a glaring unmet need to develop and test through preclinical studies novel targeted agents and combinations with superior efficacy that can be advanced to the clinical setting in AML with MLLr or mtNPM1. FHD-286 is the first in clinic (NCT04891757), potent, catalytic inhibitor, whereas AU15330 is the PROTAC (Proteolysis Targeted Chimera) degrader of BRG1/BRM. Our preliminary studies demonstrate that treatment with FHD-286 induces differentiation and lethality in AML cells, regardless of sensitivity to MI, but not in normal progenitor cells. This compelling efficacy is associated with gene-expression perturbations responsible for growth inhibition, differentiation, and depleted AML-initiating potential in patient-derived (PD) xenograft (PDX) models of AML with MLLr or mtNPM1. FHD-286 monotherapy, and in combinations with standard and investigational agents, also exerts potent efficacy in cellular models of AML harboring MLLr and mtNPM1 with or without FLT3 mutations. Studies proposed here are supported by these compelling preliminary findings and our access to the pre-treatment and upon-relapse AML cells from patients enrolled on MI monotherapy. These studies are motivated by the overarching hypothesis that treatment with BRG1/BRM antagonist will undermine dysregulated gene expressions and overcome differentiation-arrest, growth advantage and survival of AML cells, as well as synergistically exert in vivo efficacy against PDX models of AML with MLLr or mtNPM1. The specific aims of studies proposed are: Aim 1: To determine pre-clinical efficacy of BRG1/BRM antagonist (an inhibitor or degrader) and associated perturbations in the epigenome and transcriptome, linked to the proteome, evaluated as the gene-expression perturbation signature of BRG1/BRM antagonist activity in PD AML cells with MLLr or mtNPM1 sensitive or resistant to MI treatment. Aim 2: To evaluate the pre-clinical efficacy of BRG1/BRM antagonist-based novel combinations, utilizing in vitro MI-sensitive PD AML cells and in vivo PDX models of AML with MLL1r or mtNPM1. Aim 3: To determine efficacy of BRG1/BRM antagonist-based combinations to overcome MI-resistance due to epigenetic/adaptive mechanisms or Menin mutations in PD AML cells with MLL1r or mtNPM1.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Head and neck cancers (HNCs) afflict over 65,000 Americans annually, with survivors often battling lingering complications from treatments like surgery, radiation, and chemotherapy. Notably, lymphedema and fibrosis emerge as prevalent post-treatment issues. Post-radiation inflammation triggers a cascade—from potentially reversible soft tissue edema and lymphedema to, more worryingly, permanent fibrosis. About 75% of radiated patients manifest lymphedema signs within three months, and between 30-50% evolve into moderate-to-severe neck fibrosis. This progression severely impacts functions like swallowing, speech, and neck movement. The diagnostic landscape currently leans heavily on manual and endoscopic assessments, which are inherently subjective and typically catch complications at advanced stages, often when fibrosis is already entrenched. However, routine head and neck CT scans herald promise for early lymphedema detection. Preliminary research points to CT indicators, such as CTLEFAT, as potential lymphedema markers. Yet, widespread clinical adoption remains elusive, primarily due to measurement time and specialized expertise requirements. Our team, harnessing computational imaging and AI, has pioneered CT-based auto-segmentation of cancer lymphatics and soft tissue structures. We posit that AI can harness pre-treatment data to tailor treatment plans, minimizing post-treatment lymphedema (Aim 1). Moreover, we propose that AI-enhanced CT tools can revolutionize lymphedema diagnosis (Aim 2) and risk assessment (Aim 3), offering precise therapeutic interventions. By anticipating and addressing the inflammation-to-edema-to-fibrosis sequence, this approach seeks to radically improve HNC patients' post-treatment quality of life.

NIH Research Projects · FY 2026 · 2025-04

Project Summary HER2 activating mutations occur in approximately 3% of NSCLC patients and more than 20 other cancer types, including breast and colon, comprising >10,000 patients annually in the U.S. More than 80 different recurrent activating mutations are observed, and are distinct from HER2 amplifications. There are currently no FDA- approved tyrosine kinase inhibitors (TKIs) for HER2 mutant cancers, and currently the only approved HER2- targeted treatment for lung cancer is the antibody drug conjugate (ADC) trastuzumab deruxtecan (T-DXd). There are two major obstacles limiting the effective use of HER2 targeted therapies for these patients. First, the different mutations vary widely in their sensitivity to HER2 inhibitors, and there is no validated approach for selecting the right HER2 inhibitor for a given mutation. Currently, trials typically select patients based on the exon in which the mutation occurs (exon-based classification, e.g. exon 20-mutant NSCLC). These criteria, however, are not based on biological evidence and we recently reported that even mutations within the same exon can vary widely in terms of their impact on kinase structure and drug sensitivity. Second, tumors may acquire resistance either through additional HER2 mutations (HER2-dependent resistance), or via HER2-independent mechanisms (e.g. resistance to the ADC chemotherapy component such as deruxtecan, so called “payload resistance”). These mechanisms are not yet well characterized, and we do not yet have a rational basis for selecting the most appropriate drug for treating resistant tumors. In a recent publication in Nature, we reported that for a related gene, EGFR, classifying mutations based on how they impact the 3-dimensional structure and drug response (a structure/function-based system) more accurately predicted drug response than a standard exon-based classification. We hypothesize that i) by using a similar structure/function-based approach, we could more accurately match HER2 mutations with effective therapies than a standard exon-based approach, and ii) by investigating HER2-dependent and -independent mechanisms of resistance, we can develop rational strategies for targeting refractory tumors. To investigate these hypotheses, in Aim 1 we will comprehensively characterize the landscape of HER2 mutations associated with response or resistance (both primary and acquired) to TKIs using established preclinical models, including the LentiMutate scanning mutagenesis, and data from clinical trials led by the MPI Dr. Heymach and others (see attached letters of support); in Aim 2 we will similarly characterize the landscape of response and resistance for HER2-ADCs, and determine to what extent resistance is HER2- vs payload-dependent. Finally, in Aim 3, we will develop a structure/function-based classification for HER2 TKIs and ADCs and test strategies for targeting treatment-resistant tumors. The project brings together a world-class team of investigators with expertise in HER2 biology, molecular modeling, and clinical trials for the overarching goal of developing more tailored and effective approaches for HER2-mutant cancers.

NIH Research Projects · FY 2026 · 2025-04

Ninety percent of cancer-related deaths are due to metastasis, rather than complications from the primary tumor. For metastatic triple-negative breast cancer (mTNBC) patients, their disease often spreads to multiple organ sites, such as the lungs, liver, and brain. This high rate of metastatic spread poses a significant challenge in managing mTNBC, as the disease's ability to disseminate to various organs leads to poorer outcomes. mTNBCs show extensive intra-tumoral heterogeneity (ITH), making it challenging to study due to both logistical and technical barriers. Logistically, it is difficult to obtain primary tumors and metastatic sites from multiple organs from a single patient. Technically, it has been difficult to resolve genetic and transcriptomic ITH from samples across multiple organ sites, which is critical for reconstructing clonal lineages and ordering the genetic events that occur during metastasis to understand models of evolution and progression. To overcome these challenges, our group has established the first metastatic breast cancer postmortem tissue collection program, ‘Final Gift Program’, at the MD Anderson Cancer Center. To overcome technical hurdles, we will leverage a new, high-throughput, nanowell method to simultaneously measure DNA and RNA in the same single cells and provide spatial context with new spatial genomic technologies. Our central hypothesis is that development of a metastatic phenotype is driven by co-evolution of cancer cell intrinsic genomic alterations and their intimate interactions with the tumor microenvironment (TME) at the primary tumor and metastatic niches at different organ sites. We will investigate the genomic evolution of primary to metastatic tumor cells by reconstructing clonal lineages and mapping phenotypic programs to the genetic lineages during metastasis. We will study metastatic precursor cells (MPCs), which are rare subpopulations in primary tumors that share features with cancer cells at metastatic sites. By studying gene expression programs found across seeded organs, we will gain insights into the molecular events that promote metastatic spread. Our proposal is organized into three synergistic aims. Aim 1 will apply an innovative DNA&RNA co-assay to study the genomic and phenotypic evolution of MPCs during metastatic dissemination. Aim 2 will investigate gene expression programs in the stromal and immune TME across multiple organ sites. Aim 3 will integrate the spatial proximity of metastatic cancer cells and TME cell types to define cancer-immune interactions within each niche. Completing these aims will greatly expand our fundamental understanding of mTNBC metastasis and the contributions from both the cancer cells and TME that promote multi-organ dissemination. The long-term goal is to uncover the genomic and transcriptomic underpinnings of metastatic spread that can be exploited to develop effective therapeutic interventions for treating or preventing metastases in mTNBC patients. This proposal directly aligns with the NIH mission to reduce the disease burden and enhance the quality of life for mTNBC patients.