University Of Tx Md Anderson Can Ctr

NIH Research Projects · FY 2026 · 2026-06

Project Summary Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by enhancing immune-based anti- tumor responses. Despite their efficacy, especially when used in combination, ICI treatment can lead to immune- related toxicities, which can affect any organ. ICI-myocarditis refers to inflammation of the heart, is a particularly severe toxicity,with high mortality (up to 50%). To better understand mechanisms of ICI-myocarditis, our groups have generated mouse models that replicate the disease both clinically and pathophysiologically. In tumor- bearing, ICI-treated mice, myocardial immune infiltration resulted in cardiomyopathy and arrhythmias; mice genetically deficient in immune checkpoints die prematurely from fulminant myocarditis. While immune dysregulation plays a critical role in ICI-myocarditis, our findings highlighted the surprising, yet essential roles of cardiac-protective factors in mitigating ICI-myocarditis. We specifically showed that Mesencephalic Astrocyte- Derived Neurotrophic Factor (MANF), secreted by the heart, plays a protective role in ICI-myocarditis with ICI downregulating MANF in the heart. This proposal aims to uncover the molecular mechanisms underlying cardiac immune privilege. Our preliminary data suggested that MANF induces expression of FGL1 (Fibrinogen-like 1), a negative immune checkpoint ligand for LAG3 (Lymphocyte-activating 3) expressed on T lymphocytes. These findings raise the intriguing possibility that direct cardiac-T cell interaction regulates immune privilege in the heart. We further provide evidence that genetic deletion of Lag3 or Fgl1 (in combination with Pdcd1) results in myocarditis, highlighting the critical role of the MANF/FGL1/LAG3 axis in the myocarditis. We hypothesize that MANF upregulates cardiac FGL1 to modulate the cardiac immune microenvironment (CIME), mitigating ICI-myocarditis while preserving anti-tumor immunity. Without this investigation, addressing the critical risk of mortality in ICI- treated patients will remain a significant challenge, hindering efforts to improve patient outcomes and minimize cardiotoxicity. Aim examines the functional importance of MANF/FGL1/LAG3 axis in ICI-myocarditis using both genetic and tumor-bearing, ICI treated mouse models. Aim 2 investigates the mechanisms underlying the MANF-induced cardiac FGL1 expression using iPSC-derived cardiomyocytes. Aim 3 dissects the crosstalk between cardiomyocytes and effector T cells derived from the same ICI-myocarditis patient. We will also define the MANF/FGL1/LAG3 expression and CIME in human ICI-myocarditis hearts; as well as mouse CIME and tumor immune microenvironment using mouse myocarditis models. The findings from this research are expected to fill critical gaps in understanding ICI-myocarditis and provide strategies to mitigate cardiac toxicity while preserving anti-tumor immunity. This study could reshape cancer immunotherapy, optimizing patient safety and improving treatment outcomes by balancing immune regulation in both the heart and the tumor microenvironment.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT Intrahepatic cholangiocarcinoma (iCCA) is a cancer of the bile ducts with an incidence rate in the United States of 1.19 persons per 100,000 per year and a devastating 9% 5-year survival rate with few therapeutic options. A critical gap in knowledge to improve outcomes in iCCA is an incomplete understanding of the impact of tumor heterogeneity on disease progression, therapeutic failure, and metastatic dissemination. Higher tumor heterogeneity can fuel resistance to therapy because of the emergence of subclonal cell populations harboring disparate molecular signatures, leading to differential responses to treatment. The overall objective of this proposal is to determine alterations in the genome, transcriptome, and tumor microenvironment that contribute to tumor heterogeneity, cancer evolution, and adaptation in iCCA. The central hypothesis is that iCCA is characterized by multiple, diverse subclonal populations within both an individual tumor and across primary and metastatic tumors within the same patient, and that this heterogeneity can underlie tumor recurrence, resistance to therapy, and metastatic progression. Specific aims are (1) to interrogate the genomic and spatial transcriptomic heterogeneity between matched human primary and metastatic iCCA and (2) to determine the impact of intratumor heterogeneity on drug sensitivity in novel mouse models of iCCA. The justification for the use of animal models is the need to investigate intratumor heterogeneity in vivo, using sophisticated mouse models carrying gene inactivations that are functionally identical to those found in human patients. These animal models are expected to enhance the discovery of drug resistance mechanisms and therapeutic vulnerabilities in human patients. The proposed project will shed critically important light on associations between heterogeneity, cancer evolution, metastasis, and therapeutic outcomes. The contribution will be significant because the impact of iCCA intratumor and intrapatient heterogeneity upon patient outcomes in the United States is currently poorly understood. Successful completion of the specific aims will lead to an improved understanding of molecular alterations and evolutionary processes that lead to recurrence after surgery, treatment resistance, and metastatic capacity. Together with our existing and proposed intratumor heterogeneity results, our investigation of metastatic evolution will robustly inform the design and delivery of targeted and immunotherapy strategies, with the ultimate goal of improving survival rates and quality of life for patients afflicted by this refractory disease.

NIH Research Projects · FY 2026 · 2026-06

Retrotransposons are interspersed genomic repeats that constitute almost half of the mammalian genome. Largely residing in the heterochromatin, retrotransposons are transiently induced during early development to regulate lineage differentiation, and kept silenced in adult terminally differentiated tissues. However, in human diseases such as cancer and aging, retrotransposons often exhibit aberrantly elevated activities, whose underlying molecular trigger and functional consequences are less understood. Murine skin represents an excellent model to study retrotransposon silencing mechanisms. As our largest organ, skin harbors highly abundant, well characterized, and genetically accessible adult stem cells. Hair follicle stem cells reside in an anatomically distinct niche known as the bulge, alternating between quiescence and activation in a synchronized fashion to fuel cyclic bouts of hair growth. Over repeated insults, hair follicle stem undergo functional exhaustion, the molecular driving events of which were often unclear. In the current proposal, I plan to examine chromatin regulators that couple adult stem cell activation with retrotransposon suppression during adult skin and hair follicle regenerations. Two central heterochromatin pathways are known to silence retrotransposons: tri-methylation on histone 3 lysine 9 (H3K9), catalyzed by histone lysine methyltransferases (KMTs), and DNA cytosine methylation, catalyzed by DNA methyltransferases (DNMTs). Moreover, lineage gene expression during stem cell differentiation depends on DNA demethylation, catalyzed by the DNA demethylase ten-eleven translocation (TET). While TETs are crucial for DNA methylome remodeling in early development, their regulations of retrotransposons in adult tissues remain underexplored. My preliminary analysis of genetic models in which the endogenous retroviruses (ERVs, a type of retrotransposons), are reactivated to drive skin stem cell exhaustion and hair loss, afforded me a unique tool to tackle these questions. Specifically, my prelim data indicated that a critical signal connecting TET to H3K9 KMT and DNMT function is the post-translational modification known as O-linked-β-N-acetylglucosamine (O-GlcNAc). I hypothesize that OGlcNAc catalyzed by the OGlcNAc transferase (OGT) is essential to suppress ERVs by interacting with H3K9 KMT and DNMT in the skin. I will examine OGT-deficient skin phenotypes and O-GlcNAc changes upon ERV reactivation, and dissect the mechanisms of OGlcNAc-orchestrated ERV suppressions. Study proposed here leverage my previous training in mouse genetics, development, epigenetics, and skin biology, and are designed to further train me with the state-of-art technologies such as CRISPR and classic methodologies in biochemistry and molecular biology. My training plan and my sponsor/co-sponsor support have been tailored to further foster my critical thinking, scientific communication, leadership and career development goals within MDACC and GSBS training environment. The proposed study, if successful, will provide important mechanistic insights into retrotransposon biology in adult skin, and mature me into an independent researcher.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Actinic keratoses (AKs) are common pre-cancerous skin lesions that can undergo transformation to cutaneous squamous cell carcinoma (cSCC), the second most common cancer in the United States. When there are multiple AKs in one body area, field treatment with the topical chemotherapy 5-fluorouracil (5-FU) for 2-4 weeks can be used, which reduces the risk of cSCC by 75%. 5-FU has substantial downsides, however: patients apply 5-FU at home for 2-4 weeks and expected effects include weeks to months of intense redness, irritation, crusting, and erosions, which can negatively impact utilization. Our prior work has shown that 5-FU is used in only 20% of patients who may have been candidates for field treatment. To address issues of duration and symptoms, 5-FU combined with topical calcipotriene, a vitamin D analog used in psoriasis, for a shorter duration of 4 days (combination treatment; ComboTx) has been proposed. A proof-of-concept trial of ComboTx showed a decrease in AKs. It is unknown whether this shorter-course ComboTx is non-inferior to the lengthier single-agent 5-FU regimen. Furthermore, the goals of using ComboTx (improved patient satisfaction, decreased symptoms) are unstudied. Comparing 5-FU and ComboTx head-to- head is critical for evidence-based AK treatment and cSCC prevention. To best center the patient experience in treating AKs to prevent cSCC, we also need rapid assessment of response, convenient to patients. Quantifying AKs using digital photography and artificial intelligence (AI)- supported algorithms could greatly improve our ability assess clinical response when treating AKs and support cSCC prevention remotely. However, it is unknown whether digital photography can be used to quantify AKs, and unclear whether an AI-supported image segmentation algorithm could automate AK quantification for telemonitoring. In Aim 1 we will perform a dual-site randomized non-inferiority clinical trial comparing 5-FU to ComboTx in patients with multiple AKs. We will evaluate both medical outcomes (e.g., change in AK count, number of cSCCs diagnosed) and patient reported outcomes (e.g., patient satisfaction, adverse events, adherence). In Aim 2 we will compare in-person counts of AK lesions to counts using standardized digital photography, explore whether an AI-supported algorithm could automate AK counts, and determine the potential of vision language models to reliably grade the severity of precancerous conditions. The results of this trial will have clinically significant implications for AK treatment and cSCC prevention, materially influence healthcare practice, and support development of novel methods for efficient clinical trial deployment around AK counts, which will be extendable to other remote monitoring applications in other skin cancer types and dermatology more broadly.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Metastasis is the leading cause of cancer-related death. Cancer development, progression and metastasis happens through an evolutionary process, selecting for tumor clones with higher growth potential, resistance to treatment and immune pressures, and increased fitness to thrive in a new environment. While the early stages of tumor evolution leading to the development of primary tumors are quite well understood, the genetic makeup and evolutionary dynamics of cancer metastases remain less explored. Deeper study of the evolution of metastatic cancer holds immense promise, potentially paving the way for interventions that could prevent as much as 90% of cancer-related deaths. The PI on this proposal, Dr. Peter Van Loo, is an expert in leveraging DNA sequencing to infer cancer’s evolutionary history. These approaches, collectively coined Molecular Archeology of Cancer, have led to important biological insight into how tumors evolve in multiple cancer types. Across cancers, they showed that intra-tumor heterogeneity is pervasive and that primary tumors evolve over many years to decades and follow somewhat ordered paths. The genomes of cancer metastases typically show higher frequencies of aneuploidy and whole-genome duplication than those of primary tumors. This both necessitates the development of molecular archeology of cancer approaches bespoke to the analysis of cancer metastases, and provides opportunities for more detailed inference. The Van Loo lab recently developed a novel chromosomal gain timing approach, GRITIC, specifically designed to time complex copy number gains in cancer metastases. Further development of these molecular archeology of cancer metastasis methods will lead to key opportunities to advance understanding of these deadly diseases. Here, we will develop novel molecular archeology of cancer approaches to elucidate the evolutionary history of cancer metastases and demonstrate their effectiveness through application to small-cell lung cancer, one of the deadliest cancer types, often diagnosed at the metastatic stage. We will achieve this in three aims: Aim 1: Develop novel clonal evolutionary timing approaches to time genomic events in metastatic cancer evolution. Aim 2: Develop novel approaches to elucidate trajectories of mutational process activity over clonal evolutionary time with fine resolution. Aim 3: Elucidate the evolutionary history of metastatic small cell lung cancer through ctDNA profiling and research autopsy.

NIH Research Projects · FY 2026 · 2026-06

Immune checkpoint inhibitors (ICIs) have significantly improved survival in many cancer patients, but most still fail to respond to these treatments. We and others have demonstrated that personalized mRNA lipid nanoparticle vaccines enhance antitumor immunity in combination with PD-1 inhibition. However, we recently found that mRNA vaccines targeting non-tumor antigens can also act as potent adjuvants to immune checkpoint blockade, leading to improved survival in non-small cell lung cancer and metastatic melanoma patients. This proposal aims to interrogate the mechanisms by which mRNA vaccines targeting non-tumor antigens generate antitumor immunity. Our overarching hypothesis is that much of the benefit of personalized mRNA vaccines is derived from their ability to broaden the T cell repertoire by enhancing DC priming of T cells in tumors and tdLNs, leading to antitumor immunity that is most magnified by CTLA-4 blockade. We will test this hypothesis through three specific aims: Aim 1: Determine the mechanism by which non-neoantigen mRNA vaccines produce tumor-reactive T cells. Aim 2: Dissect the mechanism by which mRNA vaccines preferentially augment antitumor responses to CTLA-4 blockade. Aim 3: Interrogate the importance of antigen selection for mRNA cancer vaccines in combination with PD-1 and CTLA-4 blockade. This study is designed to offer a transformational shift in our understanding of mRNA vaccines, highlighting their potential not only as tumor-targeting agents but also as powerful adjuvants for immune checkpoint blockade. Ultimately, this research aims to leverage the innate adjuvanticity of mRNA to facilitate the development of universal cancer vaccines.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Accurate risk assessment is essential for guiding clinical decision-making in rare cancer cases, especially within a specific medical institution, due to variability and heterogeneity across institutions. However, the limited sample sizes typically available for rare cancers in a single institution present significant challenges for survival analysis. The primary objective of this research program is to advance statistical methods that enhance risk assessment for a target cohort by adaptively leveraging information transferred from external source cohorts. This research focuses on a common scenario where the target cohort from a single institution collects more detailed covariates—such as newly developed biomarkers and comprehensive genetic information—than the external cohorts sourced from cancer population registries or research consortiums. Conventional methods often assume that both cohorts share the same covariates, which limits their applicability when crucial covariates are missing in the source cohorts. To address these limitations, we propose two transfer-learning frameworks that adaptively borrow information from the source cohort while accounting for differences in covariates and time-dependent hazards. Our specific aims are: (1) develop a novel transfer-learning-based Cox model that accommodates the absence of key covariates in the source cohort, enabling effective information transfer; (2) create a group-specific transfer-learning-based Cox model that allows for flexible information borrowing at the subgroup level when heterogeneity between the target and source cohorts varies across subgroups; and (3) develop and disseminate publicly available, user-friendly software packages to ensure the reproducibility and application of our methods across multiple datasets. Although the proposed methodology is agnostic to disease type, we will demonstrate its utility in the context of inflammatory breast cancer (IBC) and myelodysplastic syndromes (MDS)—both of which are rare, aggressive cancers—making them ideal proof-of-concept cases for our methods. Overall, this project aims to advance statistical methods in personalized risk prediction and treatment strategies by facilitating adaptive knowledge transfer from external data sources, even when cohort discrepancies exist. More importantly, this work has the potential to significantly improve risk prediction and treatment selection for rare cancer types, ultimately helping clinicians develop optimal, patient-specific treatment strategies.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a five-year survival rate under 12%. More than 80% of PDAC tumors harbor oncogenic KRAS mutations, most commonly KRASG12D. Although recent development of oncogenic KRAS inhibitors represents a significant therapeutic advance, early clinical and preclinical studies have revealed only modest and transient responses, underscoring an urgent need to better understand resistance mechanisms and identify combinatorial treatment strategies. Emerging evidence suggests that co-occurring tumor suppressor gene (TSG) alterations, particularly in CDKN2A and SMAD4, may profoundly influence tumor behavior and therapeutic response. These TSGs are frequently inactivated in KRASmutant PDAC and are associated with worse prognosis, increased metastatic potential, and poor response to therapy. However, how these genetic contexts modulate resistance to KRAS inhibition remains poorly defined. This proposal aims to elucidate the role of TSG deficiencies in modulating therapeutic response to oncogenic KRAS inhibition and to identify new vulnerabilities for precision therapy tailored to specific context of TSG deficiencies. In the K99 mentored phase (Aim 1), I will use isogenic patient-derived organoid (PDO) and xenograft (PDX) models to investigate how loss of CDKN2A or SMAD4 alters PDAC cell state transition and tumor-intrinsic responses to oncogenic KRAS inhibition. I will profile treatment-induced transcriptional rewiring and validate phenotypes in vivo using orthotopic xenograft models. In the R00 independent phase (Aim 2), I will employ single-cell RNA sequencing and spatial transcriptomics and proteomics to characterize how TSG deficiencies shape the cellular and spatial landscapes of PDAC tumors under KRAS inhibition. This will uncover resistant cell states and spatially organized regulatory networks. In my R00 phase (Aim 3), I will also assess the efficacy and durability of combined KRAS inhibition with triple immunotherapy (KRASi + Triple-IO) across a complete allelic series of genetically engineered mouse models (GEMMs) harboring individual or combined loss of TP53, INK4a/ARF, and SMAD4. I will also conduct comprehensive molecular and immune profiling of tumors from these survival cohorts to elucidate how tumor suppressor genotypes influence therapeutic response and drive mechanisms of relapse. Together, this integrated approach will provide mechanistic insight into KRAS inhibitor resistance and tumor immune microenvironment reprogramming driven by TSG deficiencies and uncover novel genotype-tailored therapeutic targets. The proposed training in organoid engineering, spatial transcriptomics, and functional genomics, combined with mentorship from experts in cancer biology and immunotherapy, will position me to launch an independent research program focused on precision oncology for PDAC. Justification for the use of animal models in this project- Cancer is a systemic disease involving complex interactions within the tumor microenvironment that cannot be fully recapitulated in vitro. Therefore, in vivo assessment is required to evaluate tumor suppressor gene function and therapeutic response, and mouse models provide a well-established and physiologically relevant platform for these studies.

NIH Research Projects · FY 2026 · 2026-05

Medulloblastoma (MB) is the most common brain cancer and a leading cause of cancer deaths in children. Mortality frequently results from leptomeningeal spread within the central nervous system. Effective, less-toxic therapies for MB and leptomeningeal disease (LMD) represent an unmet need; survival has not improved significantly for decades and patients who are cured are afflicted with lifelong treatment-associated sequalae. Our overarching goal is to change the clinical practice paradigm by developing less-toxic, more effective therapies to improve survival and quality of life for children with MB and LMD. To this end, we recently reported in New England Journal of Medicine that engineered oncolytic herpes simplex virus (oHSV) G207 was safe with promising efficacy and generated a robust intratumoral cytotoxic T cell immune response in a pediatric high- grade glioma (pHGG) phase 1 trial (NCT02457845). Further, in preclinical studies in MB-LMD, we demonstrated safety and heightened efficacy of G207 (compared to pHGG), leading to an ongoing phase 1 trial in recurrent malignant cerebellar tumors (NCT03911388). Despite favorable results in our studies, most responders unfortunately progressed over time, albeit slower than expected. Therefore, novel strategies to augment and sustain the anti-tumor immune response initiated by G207 and to prevent tumor immune evasion are needed to achieve durable responses. In our recent publication in Nature Cancer, we identified tumor cell expressed Ring Finger Protein 2 (RNF2) as a master immune suppressor. We found that RNF2 is overexpressed in MB and LMD and is associated with a significantly worse prognosis and immune suppression. Deleting tumoral RNF2 in murine cancer models resulted in long term tumor regression mediated by mobilized CD4+ T (Th1 skewed) cell- dependent anticancer immunity. Since mobilized CD4+ T cells are shown to inhibit MB growth and metastases, and to induce, facilitate and support CD8+ CTL response, which G207 stimulates, we hypothesize that RNF2 inhibition will be a novel and effective therapeutic strategy for treating MB-LMD and will synergize with oHSV to achieve durable responses. We will test this hypothesis by accomplishing the following specific aims: Aim 1: investigate the anticancer activity of tumoral RNF2 inhibition in MB-LMD; Aim 2: define the anticancer functions of CD4+ T cells in RNF2 inhibition in MB-LMD; Aim 3: determine the synergy of RNF2 inhibition with oHSV in MB-LMD. Upon completing these aims, we will have demonstrated the safety and effectiveness of targeting tumoral RNF2 alone and combined with oHSV to treat MB-LMD and induce durable anticancer immunity. This contribution will be significant and innovative since it will establish a new tumor target (RNF2) in MB-LMD, leading to the development of an innovative combinatorial immunotherapy and resulting in new clinical trials to treat children afflicted with MB-LMD, who desperately need improved, targeted treatments. Our findings will likely be applicable to other pediatric brain and solid tumors, increasing the overall impact.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT As a tumor evolves, its cells can take on distinct identities that distort the lineage expression programs of their normal counterparts. In cholangiocarcinoma (CCA), a highly lethal and treatment-resistant cancer of the bile ducts, we show for the first time that ongoing lineage plasticity occurs in patient samples and is functionally connected to tumor aggressiveness phenotypes. These novel insights open the opportunity for exploiting lineage plasticity as a new source of biomarker and therapeutic discovery. To do so, we propose a comprehensive and systematic creation of a functional landscape of CCA lineage plasticity, dissecting both its regulators and its impacts on malignancy and drug response. The base blueprint of this landscape will come from extensive RNA and chromatin data generation, upon which will be layered mechanistic, drug vulnerability, and in vivo tumor data. Our long-term goal is for our landscape to serve as a foundational roadmap for future CCA research efforts to project their data onto and gain clinically-relevant guidance. Specifically, our aims will 1) dissect the proximal regulators of lineage plasticity, by perturbing lineage-specifying transcription factors and by conducting cutting-edge spatial epigenomics of patient samples; 2) leverage our newly-discovered roles of the tumor suppressor genes ARID1A and BAP1 in regulating lineage plasticity to more deeply understand their mechanisms of action, therapeutic vulnerabilities, and in vivo impacts in new mouse models; and 3) harness the collected data and innovative bioinformatics to construct a lineage plasticity landscape that interconnects dense sequencing data with functional wet lab assays and mouse modeling data. In sum, our deliverables include new drug targets and mouse models, deep patient sample data, chromatin regulatory mechanisms, and a unified view of how the subversion of normal developmental programs in cancer can be exploited to advance translational oncology.

NIH Research Projects · FY 2026 · 2026-05

Progressive telomere shortening, which occurs over humans' natural lifespan, is a primary molecular cause of the functional decline of stem cells in high-turnover tissues, including hematopoietic stem cells (HSCs). However, how telomere damage compromises HSCs’ functions is largely unknown. Here, we propose investigating the molecular mechanisms behind telomere damage–induced functional HSCs’ decline to uncover therapeutic strategies to ameliorate bone marrow (BM) failure disorders. In preliminary studies, we demonstrated that telomere damage does not activate programs of apoptosis or senescence in HSCs but instead induces their aberrant activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of Ifi20x/IFI16-mediated innate immune signaling response, which directly compromises HSCs’ self-renewal capabilities and eventually leads to their exhaustion. Given that HSCs’ exhaustion in the context of BM failure disorders predisposes to clonal selection, we evaluated whether telomere shortening–induced DNA damage in patients with germline mutations affecting telomere maintenance genes who developed telomere biology disorders (TBDs) is associated with clonal hematopoiesis (CH). We studied the architecture, trajectories, and impact of CH in a cohort of 207 TBD patients. CH was rare in asymptomatic patients but present in 46% of symptomatic patients and involved chromosome 1q aberrations (mainly chromosome 1q gain [Chr1q+]) and recurrent mutations in PPM1D, POT1, TERT promoter, and U2AF1S34. Compared with age-matched healthy controls, patients with TBDs had a significantly higher CH frequency, which increased with age. Regardless of allele burden, Chr1q+ and mutations in U2AF1S34 or TP53 increased the risk of developing myelodysplastic syndromes and acute myeloid leukemia. Further functional studies demonstrated that the U2AF1S34 mutation compensated for the aberrant activation of the TP53 and interferon pathways, which contribute to HSC exhaustion in patients with TBDs. These results suggest that the acquisition of U2AF1S34 mutations in TBDs compensates for the restricted cell fitness caused by germline mutations in telomere maintenance genes, which underscores the importance of understanding the molecular mechanisms of U2AF1S34 mutation–induced tumorigenesis. In this proposal, we will use innovative technologies, such as organoid and induced pluripotent stem cell systems and the MISTRG mouse model to 1) Dissect the IFI16-mediated signaling pathway under telomere attrition and determine the feasibility of targeting IFI16 in humans to rescue telomere-dysfunctional HSC function and 2) Dissect the mechanisms of U2AF1S34 mutation–induced tumorigenesis under telomere stress. The proposed study will expand our understanding of the contribution of telomere damage to HSCs’ functional decline and CH and provide new opportunities for developing strategies to improve the prevention and treatment of hematological disorders associated with telomere dysfunction.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Renal cell carcinomas (RCC), particularly clear cell renal cell carcinoma (ccRCC), are among the most chemotherapy-resistant cancers, driven predominantly by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene in over 90% of cases and leads to the stabilization of hypoxia-inducible factor 2α (HIF2A), triggering widespread changes in gene expression, metabolic reprogramming, and angiogenesis. While advancements in systemic therapies targeting the VEGF pathway and immune checkpoints have shown promise, understanding intra-tumoral heterogeneity and its impact on therapy resistance remains a significant challenge. Cellular function is intricately dependent on its local environment, yet bulk and single-cell profiling lacking the spatial resolution necessary to decipher the complex biomolecular and cellular interactions within the native tumor microenvironment. This proposal seeks to address critical knowledge gaps by leveraging spatially resolved transcriptomics, genomic engineering, and multi-omics methodologies to create a comprehensive spatial atlas of treatment-resistant ccRCC. Specifically, the study hypothesizes that therapy-driven sub-clonal selection promotes aggressive phenotypes, characterized by the extinction of HIF signaling, with spatially distinct subclones exhibiting unique cellular states and molecular dependencies. By integrating cutting-edge self-barcoding technology and spatial multi-omics, the project will identify sub-clonal transcriptomic fingerprints and spatial heterogeneity across the ccRCC tumor landscape. The proposed research will generate cross-species spatially resolved multi-omics data to map tumor evolution trajectories, identify molecular drivers of treatment resistance, and unravel interactions between cancer cells, immune components, and stromal elements. These insights will pave the way for the discovery of novel biomarkers to stratify patients likely to benefit from HIF inhibitors and uncover new molecular dependencies essential for the survival of HIFi-resistant cancer cells. By bridging spatial and molecular insights, this work has the potential to transform therapeutic strategies and improve outcomes for ccRCC patients.

NIH Research Projects · FY 2026 · 2026-04

Proline tRNA biogenesis as oncogenic drivers and therapeutic target in T cell acute lymphoblastic leukemia Although transfer RNAs (tRNAs) have emerged as dynamic and significant regulators of cancer progression, a critical gap in knowledge still remains in defining the mechanisms linking tRNA deregulation to tumor pathogenesis and therapy resistance. The long-term goal is to define the role of tRNA deregulation in the biology of cancers with T cell acute lymphoblastic leukemia (T-ALL) as a disease model. Preliminary studies highlight that upregulated proline tRNA biogenesis contributes to T-ALL proliferation and viability. Specifically, expression of the bifunctional glutamyl-prolyl-tRNA synthetase (EPRS1) and tRNA-Pro isoacceptors (tRNAs with different anticodons but carry the same amino acid) is significantly upregulated in primary T-ALL samples relative to thymocytes and mature T cell subsets from healthy individuals. Pharmacological inhibiton of the prolyl tRNA synthetase (ProRS) activity of EPRS1, which aminoacylates proline tRNA isoacceptors with the cognate amino acid proline, induced cell death in T-ALL in vitro compared to T cells from healthy donors. Global proteomic analysis following ProRS inhibition identified singnificant decrease in the expression levels of proline rich oncogenic proteins, highlighting deregulated proline tRNA biogenesis as a critical adaptation in the establishment of oncogenic gene expression programs in T-ALL. The overall objectives in this application are (i) to determine the molecular mechanisms by which upregulated proline tRNA biogenesis promote oncogenic gene expression programs in T-ALL and (ii) determine the oncogenic role of this pathway in vivo. The rationale for this project is that mechanistic understanding of the role of proline tRNA biogenesis in T-ALL pathogenesis will provide a strong scientific framework to develop new cancer therapeutics targeting tRNA. The central hypothesis is that upregulated proline tRNA biogenesis is critical for initiation and progression of T-ALL. This central hypothesis will be tested using two specific aims: 1) Mechanistic dissection of the role of upregulated proline tRNA biogenesis in T-ALL and 2) Define the role EPRS1 in T-ALL initiation and progression using genetic murine models. In the first aim, proline tRNA biogenesis will be perturbed using orthogonal approaches in vitro (ProRS inhibition and CRISPRi silencing of tRNA-Pro genes) in cell line models and profiled using tRNA-Seq (RNA-seq), ribosome density profiling (Ribo-Seq) and total RNA-seq to identify changes in mRNA translation sensitive to proline tRNA expression and aminoacylation levels at single codon resolution. For the second aim, genetic murine models will be used to conditionally delete Eprs1 to test the effects of loss of Eprs1 in T-ALL initiation and progression. The research proposed in this application is innovative, because it explores previously overlooked roles of leukemic cell-intrinsic tRNA dysregulation in the development of T-ALL. Relapsed/refractory T-ALL with dismal prognosis remains a clinical urgency. The proposed research is significant because it paves the way for the development of novel cancer therapeutics focused on targeting tRNA regulatory pathways downstream of oncogenic activation in T-ALL and likely other cancers.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Fusobacterium nucleatum (Fn), a bacterium typically found in the human oral cavity and a rare member of the lower gastrointestinal tract microbiota in healthy individuals, is significantly enriched in human colorectal cancer (CRC) tissues. Extensive epidemiological studies have established a strong association between high Fn levels within CRC tumors and disease recurrence, metastasis, and poor patient prognosis. However, Fn does not exist alone within these tumors; it coexists with a specific group of anaerobic bacterial species. Our previous work demonstrated the persistence of both Fn and these co-infecting bacteria in distant metastases of CRC patients and in CRC patient-derived xenografts (PDXs). Additionally, antibiotic treatment of PDXs effectively reduced intratumoral microbial load and slowed tumor growth, emphasizing the integral role of Fn and co-infecting bacterial communities within the CRC tumor microenvironment (TME). Despite these findings, the field of cancer microbiome research has predominantly focused on bulk tissue molecular analysis, resulting in a fundamental gap in our understanding of the spatial and cellular interactions between Fn, co-infecting bacteria, and human components within the TME. Recent discoveries by my team have revealed that Fn and co-infecting bacteria exhibit a heterogeneous distribution within human CRC tumors, localized to distinct tumor niches. These infected regions are characterized by myeloid cell infiltration, upregulation of immune checkpoint proteins PD1 and CTLA4, and reduced T-cell infiltration. Our central hypothesis posits that Fn and specific co-infecting bacteria collectively reshape their infected CRC tumor niche by influencing cancer epithelial cell functions and the spatial distribution of immune cells in infected regions; ultimately driving cancer progression. To test this hypothesis, we will leverage cutting-edge spatial omics techniques to investigate how the composition, load, and spatial distribution of Fn and co-infecting bacteria affect the function and spatial organization of host cellular components within the TME of both human and murine CRC tumors (Aim 1). Furthermore, we will dissect host-bacterial interactions at the single-cell level to reveal specific host cell types susceptible to invasion by Fn and co-infecting bacteria within the CRC TME and determine how these intracellular bacteria alter host signaling pathways at the single-cell level (Aim 2). My team has the breadth of experience to accomplish this project as it relates to the multiomics nature of analyses for Fn, co-infecting bacteria, and host interactions within the CRC TME. Successful completion of this proposal will bridge a critical knowledge gap in our understanding of how Fn and co-infecting bacteria shape their infected niche and influence cancer cell behavior in both primary and metastatic CRC. This research holds the potential to reveal novel therapeutic targets for inhibiting Fn-associated CRC progression or enhancing existing CRC treatments. While our primary focus is on CRC, the host-microbiota mechanistic insights gained from this study are likely to have broader implications for infection-associated cancers.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The surgical resection of liver tumors is the only solution for long-term tumor-free survival. The quality and vol- ume of the future liver remnant (FLR) are the criteria for resectability. If the FLR volume is insufficient, there is a high chance that patients will develop small-for-size syndrome, which increases the risk of post- hepatectomy liver failure, resulting in significant morbidity and mortality. Novel interventions, such as portal vein emboliza- tion or ligation, have been used to increase the FLR, with limited success. Obeticholic acid (OCA), a novel semi-synthetic bile acid analogue, shows evidence of enhancing liver growth by promoting hepatocyte prolifer- ation, reducing inflammation and fibrosis, improving bile homeostasis, and regulating lipid metabolism. OCA thereby increases the number of patients who are potential surgical candidates; however, challenges in drug dosing of OCA lead to unwanted hepatoxicity and diminished efficacy. Three urgent needs are addressed by this proposal: devising an effective and efficient delivery system that improves the controlled retention and therapeutic benefits conferred by OCA, developing a clinically translatable animal model to understand the mechanism of action of OCA and the novel delivery system in relation to liver hypertrophy, and developing a non-invasive imaging modality to evaluate FLR growth and tumor progression. Therefore, this proposal aims to (1) develop a rat tumor model with a cirrhosis background, (2) fabricate resorbable polymeric scaffolds with optimal physicochemical properties for the sustained delivery of OCA, and (3) utilize [18F]FSPG, a novel radio- tracer, for in vivo positron emission tomography monitoring of post-intervention FLR growth and tumor progres- sion. We will then correlate imaging findings with histologic and transcriptomic profiles of the liver and the tu- mor to provide mechanistic insights as to how OCA treatment affects liver growth. The proposed work is sig- nificant and innovative because there is currently no available in vivo model of portal vein ligation in the con- text of hepatocellular carcinoma and cirrhosis, and the step-by-step optimization of the physicochemical prop- erties of the polymeric scaffold will improve OCA delivery and efficacy, thus enhancing liver growth and regen- eration. Our long-term goal is developing resorbable delivery materials that help in liver regeneration, thereby increasing the number of patients who are suitable for surgical resection while furthering our understanding of how drug-polymer constructs exert therapeutic efficacy. Given the potential of OCA to modulate pathologic in- flammation, we can expand our research into other disease processes that follow a progression from inflam- mation to fibrosis to permanent end-organ dysfunction (e.g., hepatitis/steatohepatitis/cholestasis to liver fibro- sis/cirrhosis, renal fibrosis to end-stage renal disease). Furthermore, while we propose to develop a construct that can sustain the therapeutic efficacy of OCA at safe levels by enveloping them within an alginate polymer, our findings could lead to the creation of other therapeutic drug/alginate combinations using mechanism-spe- cific compounds (e.g., anti-inflammatory compounds, antioxidant compounds, matrix-degrading agents).

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY While gut microbial communities are implicated in the development and progression of metabolic dysfunction- associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, significant gaps remain in translating this knowledge into patient benefits. Prior studies have focused on species-level data and bacterial presence, largely overlooking strain-level heterogeneity, gut viral contributions, microbial transcription, and biochemical activity. These limitations hinder our ability to understand microbial mechanisms and ultimately identify therapeutic targets aimed at microbiome modulation. The overall objective of this proposal is to comprehensively investigate gut microbial communities by leveraging the largest compiled cohort to date and using a multi-omic framework to gain deeper insights into microbial genetics and molecular functions in MASLD. This project will integrate metagenomic, metabolomic, and metatranscriptomic analyses to explore microbial functional roles in MASLD and identify metabolic pathways linked to disease etiopathogenesis. Specifically, we will conduct a metagenomic systematic review and meta-analysis of internal and publicly available datasets to identify harmonized strain-level and viral signatures associated with MASLD. This will allow us to assess strain- specific differences and viral determinants in the gut microbiome that may contribute to MASLD, uncovering key microbial factors involved in disease modulation. Further, we will leverage stool metagenomic, metabolomic, and metatranscriptomic collections from the MICRObiome Among Nurses (MICRO-N), a subcohort from the Nurses’ Health Study II, which includes decades of longitudinal dietary and lifestyle data, and confirm findings using the Human Microbiome and Cardiometabolic Health Consortium (MicroCardio) and publicly available datasets. Using novel yet established computational tools, we will generate a prioritized list of microbial candidates based on transcriptional and metabolic activity, focusing on functional relevance rather than simple presence or abundance. To validate these findings, we will conduct in vitro experiments to characterize microbial metabolism and provide mechanistic insights, facilitating the discovery of microbial enzymes involved in MASLD metabolism and highlighting novel bacterial contributions to disease etiopathogenesis. This integrated multi-omic and experimental approach will greatly advance MASLD microbiome research, laying the foundation for future translational studies, including gnotobiotic experiments and clinical trials to validate microbially-driven targets contributing to MASLD. This project aligns with the National Institute of Diabetes and Digestive and Kidney Diseases' (NIDDK) mission and vision, addressing the rising burden of MASLD, which is closely linked to obesity and increases the risk of hepatocellular carcinoma (HCC). Under the mentorship of a multidisciplinary research advisory committee, the candidate will develop expertise in multi-omic computational methodologies and microbiology, establishing a unique independent research program positioning the candidate to lead future interdisciplinary investigations in microbiome science and chronic liver disease epidemiology.

NIH Research Projects · FY 2026 · 2026-03

Project Summary PPP2R1A encodes the -isoform of the scaffolding A subunit of the protein phosphatase 2A (PP2A) enzyme. PPP2R1A is mutated in >1% of cases across diverse human cancer types. Notably, PPP2R1A mutations are often observed in gynecological cancers. For example, PPP2R1A mutation occurs in up to 40% of uterine serous endometrial carcinoma (USC) and ~10% of ovarian clear cell carcinoma (OCCC). There are currently no effective therapeutic strategies based on PPP2R1A mutational status. Our unbiased screen show that PPP2R1A-mutated gynecological cancers are selectively sensitive to the inhibition of KAT6A, a histone lysine acetyltransferase. KAT6A inhibition induces cellular senescence, a state of stable cell growth arrest, in a PPP2R1A mutation dependent manner. Thus, the overall goal of this proposal is to develop urgently needed novel therapeutic approaches for PPP2R1A-mutated gynecological cancers by targeting the epigenetic regulator KAT6A. In addition, our preliminary data from both preclinical studies and a clinical trial show that immune checkpoint blockades (ICBs) are effective in PPP2R1A-mutated OCCCs. Hence, the objectives of this application are to investigate the mechanistic basis by which PPP2R1A mutant renders cancer cells selectively sensitive to KAT6A inhibition and to explore KAT6A inhibitor-based combination therapeutic strategies for PPP2R1A-mutated cancers. Our central hypothesis is that PPP2R1A-mutated gynecological cancers can be treated and ultimately eradicated by targeting KAT6A in combination with ICBs such as anti-PD-L1 or senolytics that selectively induce apoptosis of senescent cells. Accordingly, two specific aims are proposed: Aim 1 is to investigate the mechanism by which PPP2R1A-mutated gynecological cancer cells are selectively sensitive to KAT6A inhibition and Aim 2 will target the KAT6A histone lysine transferase activity for developing novel therapeutic strategies for PPP2R1A mutation. The proposed studies are highly novel because they explore urgently needed novel therapeutic strategies for PPP2R1A-mutated gynecological cancers by targeting KAT6A using clinically applicable inhibitors in combination with FDA approved senolytics such as ABT263 or immune checkpoint blockade such as anti-PD-L1 antibody. Thus, these results have the potential to develop the first effective therapeutic strategies for PPP2R1A-mutated cancers. The research proposed is of high impact because it will lay the critical foundation for ultimately developing urgently needed therapeutic strategies for eradicating PPP2R1A-mutated cancers. Therefore, the current study will not only provide critical mechanistic insights into the role of PPP2R1A mutation in cancer but will also have far-reaching implications for the development of PPP2R1A mutation-based therapeutic strategies. Further, PPP2R1A mutation occurs across many cancer types including major cancer types. The mechanistic insights gained from the proposed studies will also have broad implications.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Seventy million people worldwide have an oral premalignant lesion (OPL) at risk of transformation into oral squamous cell carcinoma (OSCC). Once transformed, 1/3 will die of OSCC. Timely identification and removal of high-risk lesions is of critical importance. Histopathologic assessment of tissue biopsies is the clinical gold- standard for estimating risk. However, diagnosis is limited by inter-rater variability among pathologists where diagnostic and subtype definitions are often inconsistent. Better strategies to improve risk stratification are needed. Genomic alterations are the primary drivers of transformation of OSCC. Current knowledge of genomic drivers has predominantly focused on early inactivation events including the deletion of chromosomal segments (e.g., loss of heterozygosity at 9p encompassing tumor suppressor CDKN2A) and the loss of tumor suppressors such as TP53. However, these inactivation events alone are insufficient for transformation into OSCC. There exists an important knowledge gap regarding how subsequent genomic events lead to selection of high-risk subclones that ultimately become OSCC. The overarching goal of this proposal is to identify and interrogate the functional importance of additional genomic events beyond early events that drive subclonal selection in oral carcinogenesis. Our primary hypothesis is that while inactivation alterations initiate clonal expansion, copy number gains and activation of oncogenes promote an increase in subclonal diversity and competition to drive transformation. This proposal leverages orthogonal approaches to comprehensively interrogate the evolution of OPL into OSCC, which include (1) the use of serial brush biopsy for OPLs, which we have shown as a non-invasive method of faithfully reconstructing subclonal architecture in both patients and mice, (2) our capability to detect persistent OPL subclones that evolve into OSCC through analysis of single cell CNAs from FFPE, (3) our ability to functionally test key mutations and chromosomal changes in primary oral epithelial cell lines, and (4) our animal models featuring spatial and temporal control of Cdkn2a loss or Trp53 mutation, crucial for studying subclonal evolution subsequent to these driver mutations. Using these innovative approaches and resources, the aims of this project are: 1. To construct the subclonal evolutionary timeline of oral carcinogenesis in patients with OPL 2. To perform functional analysis of convergent genomic alterations identified in dominant subclones 3. To understand the functional impact of additional driver mutations occurring after Cdkn2a loss or Trp53 mutation in promoting OSCC This project will provide a comprehensive analysis of subclone evolution in oral carcinogenesis, with the goal of leveraging this knowledge to improve risk stratification and prevention strategies.

NIH Research Projects · FY 2026 · 2026-02

Osteoradionecrosis (ORN) of the jaw is a severe complication of radiotherapy (RT) in head and neck cancer patients, leading to significant oral dysfunction and compromised quality of life. Early detection is critical for timely intervention, yet current clinical methods often fail to identify ORN before irreversible damage occurs. This F31 project leverages Al-powered radiographic analysis to enhance ORN detection and management by developing predictive models and automated tools to assist clinicians. In Specific Aim 1, I will establish a clinical benchmark by evaluating the consistency of clinician assessments of radiographic ORN. This benchmark will provide a gold standard for comparison with Al-based models. Specific Aim 2 will focus on developing an automated segmentation tool to segment ORN on radiographic images, using physician-generated contours as the ground truth. Specific Aim 3 involves building a predictive model based on radiographic density changes {delta-HU) to identify patients at higher risk of ORN early in the treatment process. The training goals of this award will provide me with essential sills in Al model development, medical imaging techniques, and clinical decision support tools, all within the specialized field of radiation oncology. Through mentorship at MD Anderson Cancer Center, an internationally recognized leader in cancer treatment and research, I will gain the expertise necessary to translate these innovations into clinical practice. This research aligns with the mission of NIDCR by advancing technology that reduces radiation induced oral morbidities, ultimately improving patient outcomes in dental and oral health related to radiotherapy.

NIH Research Projects · FY 2025 · 2026-01

PROJECT SUMMARY Osteosarcoma, the most common primary malignant bone tumor in children, begins in the cells that form bones and has the potential to rapidly metastasize if not diagnosed early. The implementation of natural killer cell immunotherapy to treat pediatric osteosarcoma lung metastases is an emerging treatment approach. However, clinicians are currently unable to verify the delivery of immunotherapy to desired target sites in the lungs, which is a critically unmet clinical need. An innovative approach for imaging immune cell delivery in vivo may provide new insight into the journey and destination of administered immunotherapy, which may lead to an increase in immunotherapy treatment-success rates for pediatric osteosarcoma patients with lung metastases. To address this clinical gap, I propose to use “hyperpolarized chemical exchange saturation transfer” (hyperCEST), a novel magnetic resonance lung imaging (MRI) strategy, to track the delivery of administered natural killer cell immunotherapy to the lungs in vivo. While traditional 1H MRI of the lungs suffers severe limitations due to low inherent tissue density, my innovative approach combines emerging, FDA approved and clinically relevant, hyperpolarized 129-Xenon gas and clinically translatable, FDA approved perfluorocarbon nanodroplets as hyperCEST contrast agents for natural killer cell labeling in the lungs. I hypothesize that labeling natural killer immunotherapy cells with perfluorocarbon nanodroplets optimized for 129-Xenon hyperCEST MRI detection will allow for non-invasive visualization of immunotherapy delivery in the lungs. To investigate this hypothesis, I will develop a 129-Xenon pre-scan calibration pulse sequence for a 7T preclinical MRI scanner in order to calibrate the MRI scanner prior to 129-Xenon imaging experiments. I will also develop a series of multi-compartment thermal 129-Xenon gas phantoms to simplify optimization of the conditions for 129-Xenon hyperCEST using perfluorocarbon-labeled natural killer cells (Aim 1). Next, I will optimize a hyperCEST saturation pulse in order to selectively saturate the frequency of dissolved-phase hyperpolarized 129-Xenon in perfluorocarbon-labeled natural killer cells and generate maximum hyperCEST contrast (CNR) in vitro (Aim 2). Finally, in vivo hyperCEST MRI using hyperpolarized 129-Xenon gas will be performed to produce a hyperCEST contrast map of the distribution of perfluorocarbon-labeled NK cells in the lungs of mice. We will validate our findings using Xerra cryo-fluorescence tomography, which will provide the distribution of fluorescent perfluorocarbon-labeled NK cells, which can be correlated with hyperCEST maps (Aim 3). The proposed training offered through this fellowship would further accentuate my existing research strengths, address gaps in needed skills such as MRI physics and pulse programming, provide mentored research experiences, grant me the opportunity to further extend my publication record, and allow me the ability to improve my scientific communication and research presentation skills. Additionally, the Magnetic Resonance Systems Laboratory is the ideal place to perform this research, as I have access to advanced MRI technologies and mentorship from my Sponsors, Drs. Bankson and Sokolov.

NIH Research Projects · FY 2026 · 2025-12

PROJECT SUMMARY Multidrug-resistant organisms (MDROs) remain major causes of morbidity and mortality in hematopoietic cell transplant (HCT) recipients. Because of the substantial use of antibiotics in these patients, their gut microbiome balance is perturbed and becomes dominated by MDROs, vancomycin-resistant enterococci (VRE) in particular. This disturbance is associated with subsequent invasive infections such as bacteremia that can lead to fatal outcome. Restoration of the normal balance of the gut flora and reduction or control of MDRO colonization may curtail these complications and improve outcomes. One innovative approach to restore the microbiome balance of the gut flora and reduce colonization with MDROs in HCT recipients is the administration of bacteriophages (i.e., phages). Phages are ubiquitous and natural entities, present in the environment and in our bodies, and capable of lysing specific pathogens without disturbing the host’s normal flora while averting the collateral damage of antimicrobial usage. My long-term research goal is to understand how phages contribute to host-microbe interactions and their overall impact on the health of HCT recipients. Our preliminary data indicate that VRE colonization can cause inflammation in the gut of germ-free wild-type mice. Additionally, we found that phages are present in high numbers in HCT patients’ stool samples and that VRE phages can be recovered from environmental samples and can lyse a variety of VRE strains in a larva model. The objective of the proposed research is to investigate the interactions between phages, the gut bacterial microbiome, and host responses in VRE-colonized HCT recipients and to identify biomarkers in the gut phage population predisposing patients to complications such as bacterial infections or graft versus host disease. The central hypothesis for this project is that VRE phages can restore balance in the gut microbiota by reducing inflammation and VRE colonization in HCT recipients. My ultimate goal is to generate significant findings and new hypotheses for an R01 application aiming at (1) optimizing the design of a chemotherapy- treated bone marrow-reconstituted mouse model mimicking the condition of HCT patients, (2) testing the efficacy of phages and phages+antibiotic synergy in preventing major MDRO infections in this mouse model, and (3) validating the role of certain phage populations in predicting and preventing poor outcomes. The rationale is that this line of work will provide supportive evidence for future development and evaluation of a phage-based intervention in humans. My long-term career goal is to become a leading investigator with expertise in the design of effective and safe phage-based natural therapeutic products that may restore a healthy gut microbiota and curtail serious complications encountered in HCT recipients (i.e., MDROs), thus improving their overall health outcomes. The proposal will aid in the fight against MDROs by curtailing the incidence of MDRO colonization and infections and by improving survival and quality-of-life of HCT recipients.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICIs) are an important advancement in oncology and have restored anti-tumor immune responses, resulting in improved survival in many cancer types. Nevertheless, there is emerging evidence that ICIs are associated with cardiovascular toxicities, including myocarditis, which has mortality rates as high as 50% in fulminant cases. Additionally, ICIs are associated with excess atherosclerotic events, such as myocardial infarction, stroke, and peripheral artery disease. Apart from toxicities associated with ICIs, there is a small group of patients who are non-responders to ICIs; many recent studies suggest that ICIs may induce various forms of immune dysregulation, which may paradoxically accelerate cardiovascular disease (CVD). Immune dysregulation is largely defined by increased oxidative stress, accumulation of reactive oxygen species (ROS), and immune cell senescence. Senescent immune cells demonstrate limited surveillance of immune responses, but also become pro-inflammatory due to a permanent change in gene expression profile termed a senescence-associated secretory phenotype (SASP), that can induce chronic inflammation, tissue damage, resist immunotherapy, and progress CVD. Based on these observations, we hypothesize that immuno- senescence is a central linking mechanism of ICI-associated cardiovascular disease (ICI-CVD) and ultimately length of survival in cancer patients. Importantly, our preliminary work suggests that immuno-senescence that preexisted prior to treatment, rather than toxicity that developed during treatment, drives cardiovascular risk and negatively impacts cancer treatment effect. For example, we found that metabolomic measures and epigenetics prior to ICI treatment predicts the development of cardiovascular events of post-ICI treatment, highlighting the value of evaluating baseline immune health prior to treatment. In order to address this clinical question, our project is a paradigm shift by combining clinical data with multi-omics biosample-derived biomarkers before and after ICI treatment, such as metabolomics, aging through epigenetic markers, and clonal hematopoiesis of indeterminate potential (CHIP), to develop predictive models that differentiate patients according to their estimated risk of ICI-CVD and cancer mortality. This systems-level approach utilizes three aims: (1) discouple the biological predictors of cardiovascular toxicity from ICI efficacy; (2) identify metabolite patterns of human monocyte-derived macrophages (HMDMs) that are associated with cardiovascular and oncologic outcomes; and (3) identify genetic and epigenetic determinants, including CHIP, of cardiovascular risk and cancer prognosis in patients receiving ICI therapy. Using this integrated strategy we aim to address clinical management by providing biomarkers that predict both subsequent cardiovascular event incidence and poor cancer outcomes. Our findings may help us determine new therapeutic interventions that separate the anti-tumor benefit of ICI from their cardiovascular risks. Moreover, we will be able to refine diagnostic criteria, and develop a grading scale for ICI- CVD that may help improve clinical decision-making in relation to continuing treatment, and ultimately improve survival, and quality of life for cancer patients receiving immunotherapy.

NIH Research Projects · FY 2025 · 2025-09

The burden of prostate cancer (PCa) is disproportionately high among Black men, who experience poor health outcomes. Black PCa survivors report lower self-perceived health, reduced quality of life, and a greater prevalence of chronic conditions. This substantial burden of comorbidity among Black PCa survivors is particularly concerning, as PCa survivors are more likely to die of these competing conditions than of PCa itself. Among the various factors contributing to the elevated survivorship burden in Black PCa survivors, lifestyle behaviors such as physical activity and healthy eating are of paramount importance, as these behaviors are modifiable. However, Black PCa survivors are less likely to be physically active and less likely to meet the national dietary guidelines. Furthermore, Black PCa survivors have had limited participation in lifestyle interventions. Thus, interventions that effectively promote these lifestyle behaviors among Black PCa survivors are urgently needed. In developing such interventions, it is important to consider the impact of family caregivers, as they play pivotal roles in supporting Black PCa survivors. However, there has been a notable absence of family-centered lifestyle interventions for Black PCa survivors. With this rationale, we have developed a lifestyle intervention for Black PCa survivors and their family caregivers that addresses physical activity and healthy eating. In a 2-arm, pilot feasibility randomized controlled trial (RCT), survivor-caregiver dyads were assigned to either an intervention or a usual-care control group. Results demonstrated recruitment feasibility and showed promise in improving moderate-to-vigorous physical activity, overall diet quality, and physical functioning (6-minute-walk test; 6MWT) in both PCa survivors and their caregivers. However, it remains unknown whether the family-centered approach is superior to an individual approach (i.e., survivor only) in improving and maintaining healthy lifestyle behaviors and health outcomes. Therefore, we propose a 3-arm efficacy RCT to compare the effects of a family-centered intervention, a survivor-only intervention, and a health education control group. The outcomes will include moderate-to-vigorous physical activity and overall diet quality (primary) and 6MWT, quality of life, and family health climate (secondary). We will also evaluate theory-based mediators and moderators of the family-centered intervention. The knowledge gained from this RCT will advance the science of behavioral medicine, and ultimately, improve the health of Black PCa survivors and their family caregivers by lowering morbidity and mortality among Black PCa survivors, as well as reducing cancer risk among caregivers.

NIH Research Projects · FY 2025 · 2025-09

Summary: Patients with relapsed/refractory (R/R) T cell malignancies have poor outcomes and novel therapies are urgently needed. While CAR-T cells have shown remarkable efficacy in patients with B-cell malignancies and multiple myeloma, targeting T-cell malignancies presents unique challenges. One of the major issues is fratricide due to the shared expression of target antigens on both malignant and normal T cells, leading to self-targeting. Additionally, there is a risk of product contamination with malignant T cells during the manufacturing process, and the prolonged life-span of CAR-T cells poses the risk of long-term T-cell aplasia. In contrast, CAR- engineered natural killer (NK) cells offer several advantages. Unlike T-cells, NK cells do not express T cell target antigens such as CD5, eliminating the risk of fratricide. CAR-NK cells also avoid the issue of product contamination with malignant cells, as they can be derived from healthy donors rather than the patient’s own cells. Their shorter life-span reduces the likelihood of prolonged T-cell aplasia. Moreover, CAR-NK cells retain their innate cytotoxicity while also providing tumor specificity against the target antigen through engineering, without the concerns of graft-versus-host disease in the allogeneic setting, cytokine release syndrome or neurotoxicity. Building on our successful first-in-human trial of cord blood (CB) derived CAR19/IL-15 NK cells in patients with relapsed/refractory B-cell malignancies (published in NEJM 2020; Nature Medicine 2024), we now propose a clinical trial targeting CD5 in T cell malignancies. Our engineered CAR-NK cells express an scFv against CD5, IL-15 to enhance persistence, and an inducible caspase-9 (iC9) safety switch (collectively termed iC9/CAR5-28ζ/IL-15 NK cells). A key innovation in this proposal is our novel ex vivo expansion protocol for CAR- NK cells, incorporating IL-12, IL-18, TGF-β and Rapamycin to enhance the metabolic fitness of the cells. Preclinically, iC9/CAR5-28ζ/IL-15 NK cells generated using this novel expansion strategy demonstrated potent activity against T-cell lymphoma models. The clinical protocol has received IRB and FDA (protocol #2021-0526, IND 30087) and is currently enrolling patients. In parallel, we will conduct state-of-the-art correlative studies to comprehensively characterize the infused CAR-NK cells, tracking their persistence, trafficking, and immune modulation in patients. Additionally, we have developed a robust genome-wide CRISPR screening platform to identify novel regulators of CAR-NK cell function and mechanisms of resistance in T cell malignancies. Insights from these studies will inform the development of next-generation CAR-NK cells, optimized to overcome immune evasion strategies and improve patient outcomes. In Aim 1 we will conduct a Phase I/II clinical trial to test the safety and efficacy of iC9/CAR5-28ζ/IL-15 NK cells in patients with CD5+ T cell malignancies. In Aim 2 we will apply comprehensive correlative studies. In Aim 3, we will perform genome-wide CRISPR screens in both our iC9/CAR5-28ζ/IL-15 NK cells and T cell malignancy cell lines to uncover novel mechanisms of resistance and inform the design of next-generation CAR-NK cell therapies.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Although studies of cell-cell interactions (CCIs) have attracted substantial attention from researchers to understand cellular development and related disease onset, considerable methodological gaps remain in assessing CCIs and their intra-sample heterogeneity in spatial transcriptomics (ST) data. This proposal is driven by our collaborative work with biologists and physicians to investigate spatially heterogeneous CCIs and their implications across various human diseases. The primary objective of this proposal is to develop robust statistical methods to quantify the heterogeneous CCI patterns on ST platforms and identify spatial or temporal differentially behaved CCIs across conditions. The project is structured around three complementary research directions. 1) We propose a novel statistical model for ST data to estimate spatial CCI patterns, overcoming limitations in existing methods. This model specifically accounts for spot-level cellular compositions and spatial location information. We will extend this model to a population scale to identify CCI patterns with differential heterogeneity across subjects with varying disease conditions. 2) We aim to incorporate spatial and temporal constraints into statistical models to detect differential CCI patterns in longitudinally collected ST data. This optimized approach will improve CCI quantification by modeling subject-specific patterns and leveraging ST data from multiple time points. 3) We will generalize our statistical method by integrating serially sectioned ST data with histological images, providing a robust solution for 3D CCI analysis. The proposed methods will be applied to ST data from pancreatic and gastric cancer patients at The University of Texas MD Anderson Cancer Center, as well as brain samples from patients with early- to late-stage Alzheimer’s disease. While initially motivated by studies of cancer and Alzheimer’s disease, these statistical methods are broadly applicable for estimating intra-sample heterogeneity of CCIs in other disease contexts and in embryo development research. Once validated, we will make all software packages developed in this project available to the wider research community. The proposed methods will bring unprecedented analytical power to characterization of cellular interactions in their surrounding environments, allowing for discovery of many hidden phenotypes that are disease- or patient outcome-associated.