Current & Past Odyssey Fellows

Haejeong An, Ph.D.

Department of Health Disparities Research 
Supported by: Theodore N. Law for Scientific Achievement

A randomized controlled feasibility trial of an adapted lifestyle intervention to mitigate accelerated aging among Black cancer survivors with obesity

Cancer survivorship in the United States has grown to over 18 million individuals, yet improvements in survival and survivorship outcomes has not been equitably distributed. African American and/or Black (hereafter Black) cancer survivors experience higher mortality, greater comorbidity burden and poorer quality of life than non-Hispanic White survivors. Accelerated aging—where biological age exceeds chronological age—is increasingly recognized as a biological consequence of cancer and its treatments, contributing to earlier onset of multimorbidity, frailty and functional decline in survivors. Among Black survivors, obesity is highly prevalent and may further intensify aging-related vulnerability by promoting metabolic dysregulation and chronic inflammatory stress, thereby compounding long-term survivorship risk. Healthy lifestyle behaviors, including physical activity and high-quality diet, represent promising and modifiable strategies to improve metabolic regulation and preserve functional capacity. However, to our knowledge, no behavioral intervention studies among cancer survivors have tested whether lifestyle modification can influence aging-related risk using phenotypic age, a clinically accessible biomarker predictive of morbidity and mortality. Most survivorship interventions focus on general behaviors rather than aging-related decline, and Black survivors remain underrepresented in trials targeting long-term survivorship risk.

To address this gap, we propose to implement and evaluate a lifestyle intervention specifically designed to target aging-related vulnerability among Black cancer survivors with obesity. Building on an existing culturally tailored lifestyle intervention originally developed for Black prostate cancer survivor–partner dyads, the specific aims of this study are to (1) systematically adapt the intervention to address obesity-related metabolic risk and aging-related vulnerability, (2) determine the feasibility of conducting a randomized controlled trial by evaluating participant recruitment and retention, and (3) assess the feasibility and acceptability of implementing the adapted intervention. Findings from this work will inform the development of a larger efficacy trial aimed at improving biological aging and long-term survivorship outcomes.

Ran Chen, Ph.D. 

Department of Experimental Radiology 
Supported by: Kimberly-Clark Foundation Award for Scientific Achievement

Chromatin-Modulating Therapeutic Interventions for Gastric Cancer Treatment

Gastric adenocarcinoma (GAC) remains a leading cause of cancer-related mortality worldwide, with limited effective targeted therapies due to profound molecular heterogeneity and aggressive metastatic behavior. Emerging evidence implicates epigenetic dysregulation as a central driver of GAC progression. NSD2, a histone H3 lysine 36 dimethyltransferase (H3K36me2), is frequently amplified, overexpressed, or mutated in GAC and correlates with poor clinical outcomes. Our preliminary studies demonstrate that NSD2 hyperactivation markedly accelerates tumor progression and metastasis, whereas genetic ablation of NSD2 suppresses tumorigenesis in multiple genetically engineered mouse models (GEMMs). Furthermore, we have developed a first-in-class, potent, and selective NSD2 small-molecule inhibitor (NSD2i) with robust in vivo activity and favorable pharmacologic properties. Thus, our Central Hypothesis is NSD2-driven epigenetic reprogramming promotes GAC progression, intratumoral heterogeneity, and therapeutic resistance and pharmacologic inhibition of NSD2 represents a viable and effective therapeutic strategy.

Ting Hong, M.D., Ph.D.

Department of Experimental Radiation Oncology 
Supported by: Theodore N. Law for Scientific Achievement

Exploiting Catecholamine Metabolism to Drive Cuproptosis and Overcome Radioresistance

Cuproptosis, a recently described form of copper-dependent cell death, has emerged as an area of growing interest in cancer research. However, compared with other well-established forms of regulated cell death, such as apoptosis and ferroptosis, the molecular and metabolic mechanisms underlying cuproptosis, as well as its therapeutic potential in cancer, remain less explored. This proposal aims to define previously unrecognized mechanisms of cuproptosis in tumor radioresistance and to assess cuproptosis inducers or sensitizers as therapeutic approaches for overcoming radioresistance. Recent studies from the Boyi Gan, Ph.D., lab revealed that tumor cell evasion of cuproptosis is a key contributor to radioresistance, and that cuproptosis-inducing therapy can overcome radioresistance in preclinical models 1. Our new preliminary data support the central hypothesis (Fig. 1) that (i) catecholcontaining metabolites in catecholamine metabolism pathway, such as L-DOPA and dopamine, potentiate cuproptosis by promoting the reduction of divalent copper (Cu²⁺) to its more toxic monovalent form (Cu⁺), and (ii) these catechol-containing metabolites synergize with radiotherapy (RT) to mitigate tumor radioresistance by augmenting cuproptosis while sparing normal tissues.

Kaelyn Dobson, Ph.D.

Odyssey Fellow (2025-2028)
Department of Comparative Medicine
Supported by: The May-Owczarek Family

Investigating Connections between the Gut Microbiome and Lynch Syndrome Mutations in Rhesus Monkeys

Animals are used to model a variety of diseases, including cancer. Non-human primate (NHP) models are commonly utilized due to the genetic, physiological, and immune characteristics they share with humans. Colorectal cancer (CRC) is considered the third most common type of cancer worldwide in humans and can be studied in NHP models. CRC in humans has two primary etiologies: genetic mutations or spontaneous instigation without genetic inheritance. The MLH1 stop-gain mutation, known as Lynch syndrome (LS), that can lead to CRC in humans is also found in rhesus monkeys housed at the University of Texas MD Anderson Michale E. Keeling Center for Comparative Medicine and Research (KCCMR). Current evidence suggests that the incidence of the MLH1 stop-gain mutation is ~ 8 percent in the rhesus monkey colony of ~ 1,000 individuals. Thus, the KCCMR rhesus colony is an excellent and unique model for studies of MLH1 stop-gain mutation-instigated CRC, including preclinical studies designed to develop interventions and treatment.

The proposed studies seek to examine, for the first time, the gut microbiome of rhesus monkeys with and without the MLH1 stop-gain mutation. The gut microbiome is the array of microorganisms found in the gastrointestinal tract (GI tract) of animals, with impacts on fitness, health, and reproductive capacities. Certain microbes are known to be associated with the initiation and progression of CRC in humans, with some linked to LS. Moreover, the gut microbiome is considered a possible cause of CRC tumorigenesis through inflammation of the GI tract. Although studies have identified associations between the gut microbiome and sporadic CRC in rhesus monkeys, none have investigated the composition of the microbiome related to LS mutations. Addressing this significant gap in the scientific literature will further establish the KCCMR rhesus monkey colony as a model organism for studies on CRC and specifically LS with significant translational applications to humans. Given that LS increases the risk of several cancers, including endometrial, ovarian, and cancers of the GI tract, this research is likely to be broadly impactful for the prevention of cancer.

Falk Ponath, Ph.D.

Odyssey Fellow (2025-2028)
Department of Immunology
Supported by: H-E-B Award for Scientific Achievement

Understanding the impact of bacterial-colonized micro-niches in the tumor microenvironment

Tumors are composed of a complex and dynamic collection of human cell types, and recent work has revealed the presence of an intratumoral microbiota within a range of solid cancer types. However, there is a fundamental lack of understanding on how microbes within the tumor microenvironment (TME) interact with human components of the tumor, or how they might contribute to disease progression, a significant barrier to progress. Our group has recently shown that viable intratumoral bacteria have a heterogenous distribution within human oral squamous cell carcinoma and colorectal tumors, where they form bacterial-colonized microniches (BCMs), dominated by the anaerobic bacterium, Fusobacterium nucleatum. BCMs exist in poorly vascularized areas that are highly immunosuppressive characterized by myeloid cell infiltration, upregulation of immune checkpoint proteins PD1, CTLA4 and Lag3, and reduced T-cell infiltration. Intratumoral heterogeneity and associated phenotypic diversification of cellular subpopulations within the TME remain a major factor for cancer progression and therapy resistance. Thus, I hypothesize that intratumoral bacteria, in the form of BCMs, directly shape intratumoral heterogeneity by influencing cellular functions, immune cell recruitment, their spatial organization, and the tumor microenvironment.

As BCMs are metabolically active components of the human TME, in this proposal I seek to harness new spatial omics technologies to meticulously map the intricate cellular and metabolic landscape of tumor BCMs and their surrounding immune environment in high resolution (Figure 1). Further, I will delineate the cellular mechanisms by which dominant species within BCMs modulate the local infiltration and function of immune cells. To test my hypothesis, I seek to carry out the following two aims over the next three years of my postdoctoral time: Aim 1 will focus on defining the spatial landscape of human solid tumors across the gastrointestinal (GI) tract. This analysis will encompass how BCMs shape the cellular, transcriptomic and metabolic topography of the TME through applying state-of-the-art spatial transcriptomics and metabolomics. Spatially dissecting the BCM is expected to characterize the immunosuppressive components of this niche and define cancer type specific and general responses to intratumoral bacteria. Aim 2 will aim at investigating the direct role of intratumoral microbiota and the BCM by applying the spatial technologies to syngeneic orthoptic mouse models colonized by the tumor-associated F. nucleatum. Leveraging both conventional and germ-free mouse models, this will assess the ability of F. nucleatum, as a representative of cancer-associated microbes, to remodel the TME in vivo.

Yalei Zhang, Ph.D.

Odyssey Fellow (2025-2028)
Department of Genitourinary Medical Oncology-Research
Supported by: Scientific Achievement- Houston Endowment

The Role of DDC in Neuroendocrine Prostate Cancer Liver Metastasis

Neuroendocrine prostate cancer (NEPC), a highly aggressive subtype of castration-resistant prostate cancer (CRPC), arises as a resistance mechanism to androgen deprivation therapy or AR signaling inhibitors (ARSi) in prostate adenocarcinoma (adeno-PCa). NEPC is characterized by hyperproliferation and widespread metastases, particularly to the liver (57.1–82% of cases), resulting the worst prognosis. Despite progress in treatment options, NEPC still lacks effective therapies. Given the high prevalence of liver metastases in NEPC patients, fully understanding its biology, and identifying novel therapeutic targets are critical for improving treatment strategies. Despite the success of immune checkpoint therapy (ICT), prostate cancer remains resistant due to its immunosuppressive tumor microenvironment (TME). NEPC, in particular, exhibits a “colder” TME than adenoPCa, as shown by prior studies12 and preliminary data. An up-regulated NEPC signature is linked to poor response to Ipilimumab (CTLA4 inhibitor) in prostate cancer patients. Brown et al. also reported poor efficacy of avelumab (PD-L1 inhibitor) in microsatellite stable NEPC/aggressive variant prostate cancer, suggesting NEPC’s consistent resistance to ICT. Liver metastasis exhibits a unique immunosuppressive TME, enriched with tolerogenic immune cells that promote immune evasion, including Kupffer cells, liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs). Liver metastases are also associated with increased infiltration of regulatory T cells (Tregs), M2-like tumor-associated macrophages (M2-TAMs), and myeloidderived suppressor cells (MDSCs), further contributing to T cell suppression. Metabolically, the nutrient-rich environment of the liver enables tumor cells to exploit lipid and amino acid metabolism for rapid growth. Thus, novel strategies are urgently needed to overcome the “cold” TME in NEPC liver metastasis. Emerging evidence highlights the key role of amino acid metabolism in ICT20 and NEPC. Our preliminary data identified DOPA decarboxylase (DDC) as the most upregulated amino acid metabolism gene in NEPC, confirmed by IHC and Western blot using PDXs, patient and mouse primary tumors. DDC, a key enzyme in serotonin and dopamine synthesis, produces metabolites including tryptamine, serotonin, and dopamine that modulate immune responses and promote cancer progression. Notably, our public data analysis links high DDC expression to poor outcomes, increased NE marker expression, and a higher frequency of liver metastases in adeno-PCa, suggesting DDC’s broader role in aggressive adeno-PCa. Importantly, DDC expression is higher in NEPC liver metastasis than in primary NEPC. Our functional studies demonstrate that DDC promotes NEPC proliferation, survival, and reduces intratumoral T cells. Given DDC’s critical metabolic role, its immune-modulatory metabolites, and our preliminary findings, we hypothesize that DDC drives metabolic reprogramming to promote NEPC liver metastasis progression through cancer cell-intrinsic and -extrinsic mechanisms. Our long term goal is to establish DDC as a therapeutic target for NEPC liver metastasis and repurposing existing DDC inhibitors to improve clinical outcomes.

Mehdi Chaib, Ph.D.

Odyssey Fellow (2024-2027)
Department of Immunology
Supported by: Theodore N. Law for Scientific Achievement

Red-Pulp-Like Tumor-Associated Macrophages Expressing Vascular Cell Adhesion Molecule 1 Drive Resistance to Immunotherapy

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) and anti-programmed cell death protein 1 (anti-PD-1), play a pivotal role in unleashing T cell control of tumors. However, their efficacy is hindered by immunosuppressive myeloid cells, particularly tumor-associated macrophages (TAMs) within the tumor microenvironment (TME). Recent technological advancements yielded tools like high-dimensional single-cell analysis, fate-mapping, and spatial transcriptomics which unveiled the intricate biology and heterogeneity of TAMs. Despite these breakthroughs, targeting TAMs in clinical settings remains challenging due to gaps in understanding TAM subset-specific adaptations to environmental cues, guided by lineage-determining and stimulus-responsive transcription factors (TFs). Consequently, understanding the biology, gene programs, and functions of TAM subsets that contribute to ICI resistance is crucial for identifying novel therapeutic targets. Preliminary findings indicate that a distinct subset of TAMs expressing vascular cell adhesion molecule 1 (VCAM-1) is increased by anti-CTLA-4 in both mice and human tumors. VCAM-1+ TAMs led to a dysfunctional activation of CD8 T cells ex vivo and promoted resistance to anti-CTLA-4 in vivo in adoptive transfer experiments. Notably, VCAM-1+ TAMs exhibit a gene signature resembling that of splenic red-pulp macrophages (RPM) which may offer clues as to the origin and function of VCAM-1+ TAMs by understanding RPM biology.

Rareș Drula, Ph.D.

Odyssey Fellow (2024-2027)
Department of Translational Molecular Pathology
Supported by: Theodore N. Law for Scientific Achievement

Extracellular vesicle encapsulated miRNAs as surrogates and conveyors of oncogenic estrogen signaling in ER+ breast cancer

Estrogen (E2) is a major driver of estrogen receptor-positive (ER+) breast cancer, accounting for over two-thirds of all breast cancer cases worldwide and representing a significant challenge in cancer management due to its role in promoting tumor growth and progression. While E2 is well known for its genomic and non-genomic signaling pathways within tumor cells, its role in shaping the tumor microenvironment (TME) through extracellular vesicles (EVs) has gained attention as a critical mechanism of intercellular communication. EVs, particularly their microRNA (miRNA) cargo, are increasingly recognized for their ability to influence recipient cell behavior, facilitating processes such as immune modulation, stromal reprogramming, and metastasis. E2 has been shown to enhance EV secretion and to regulate the selective enrichment of specific miRNAs, such as the let-7 family, which are associated with metabolic status and clinical characteristics, including menopausal state and body mass index. These miRNA-enriched EVs have been implicated in modulating immune responses, such as altering macrophage activation, potentially promoting immune evasion within the TME. The broader influence of E2-regulated EVs on tumor progression and immune dynamics underscores the importance of defining their miRNA composition and functional roles in ER+ breast cancer. Research into E2-regulated EVs also extends to adipocytes, a key source of extragonadal E2 in the breast stroma, particularly in obesity. Adipocyte-derived E2 and its impact on EV cargo represent an important area of study, given the established link between obesity, E2 levels, and poor breast cancer outcomes. Investigations into the interplay between tumor-derived and adipocyte-derived EVs are expected to clarify how hormonal and metabolic factors converge to influence the TME and tumor progression. Validation of findings in EVs isolated from patient samples is being pursued to establish their clinical relevance, particularly as non-invasive biomarkers for disease progression, therapeutic response, and relapse. In addition to identifying potential diagnostic applications, the study of EV miRNAs aims to uncover their contributions to tumor-promoting paracrine signaling networks. This research addresses critical gaps in understanding the indirect effects of E2 signaling, offering insights into how EVs mediate communication between tumor cells, adipocytes, and immune cells, and highlighting their potential as targets for novel therapeutic interventions in ER+ breast cancer.