Current & Past Odyssey Fellows

Juan Jose Rodriguez-Sevilla, M.D.

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

Hypomethylating Agent-Based Therapy Resistance in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are heterogeneous clonal disorders of hematopoietic stem cells (HSCs). Hypomethylating agent (HMA)-based therapy, the current standard of care for patients with MDS, fails in nearly 50% of patients. These patients, whose disease invariably progresses to severe cytopenias or secondary acute myeloid leukemia (sAML), have a dismal prognosis because of the lack of approved second-line treatment options. Studies investigating whether MDS patients’ genetic alterations can predict their clinical outcomes following HMA-based therapy have yielded inconsistent results, which suggests that genetic alterations alone minimally account for therapy outcomes. Given that MDS are phenotypically heterogeneous, the only way to gain a better understanding of the mechanisms underlying HMA failure and enabling the development of new therapeutic strategies to halt disease progression is to dissect the biological properties of the MDS HSCs, the disease’s cells of origin, in large cohorts of patients.  Previous work from the Colla Lab (Nature Medicine, March 2022) demonstrated that the hematopoietic stem cell populations that originate MDS have distinct differentiation phenotypes and associated signaling and survival pathways. The specific aims of this project are to 1) uncover predictive biological and molecular biomarkers of venetoclax response and resistance in prospective clinical trials and 2) dissect the immune system’s contribution to the therapeutic effect of venetoclax in sAML. 

Ryan Mulqueen, Ph.D.

Odyssey Fellow (2024-2027)
Department of Systems Biology
Supported by: Cockrell Foundation Award for Scientific Achievement

Epigenomic response to copy number alterations in early breast cancer

Tetraploidization of the genome, known as whole genome doubling (WGD), may be the most dramatic copy number variation (CNV) event in cancer. WGD occurs in 44% of breast cancer tumors, and ~1/3rd of all tumor types, across cancers. One theory is that WGD confers a “genomic buffer” to explore evolutionary space during progression to aggressive cancer. All major driver mutations of invasive breast cancer, including WGD have been identified in premalignant tissue. Though premalignant carcinoma increases the risk of invasive cancer by 10-fold, only 5% of untreated cases progress within 10 years, therefore, the transition to invasive cancer is reliant on mechanisms beyond mutation. This proposal is set to investigate a mechanism with a currently unknown role ¾ the epigenomic response to gene dosage changes. Our central hypothesis is that WGD/CNV events disrupt the epigenome across cancer-relevant genes and this disruption persists through many cell generations.

Three obstacles have hindered the study of this phenomenon: 1) heterogeneous cell states, due to rapid epigenomic response; 2) diverging lineages, due to high mutation rates after CNVs/WGD; 3) difficulty in capture of initiating CNV/WGD events in patient samples, due to occurring as early driver events.To overcome these difficulties, I will use the support of the Odyssey Fellowship to develop new single cell co-assay technologies to study cell lines models and patient samples. Thousands of single cell profiles from induced WGD in cell culture will generate a nuanced progression of epigenetic responses, addressing the first obstacle. I will measure expression (RNA), genome conformation (Hi-C), chromatin accessibility (ATAC), and methylome (MET) changes, each paired to whole genome sequencing (scWGS) in the same cell, providing lineage information and thus overcoming the second obstacle. Finally, I will develop a scWGS/MET method for formalin-fixed paraffin embedded (FFPE) tissue, allowing capture of early precancerous events, addressing the third. Together these advances will vastly improve our understanding of CNV and WGD events in early breast cancer progression.

Chenchu Lin, Ph.D.

Odyssey Fellow (2023-2026)
Department of Bioinformatics and Computational Biology
Supported by: Odyssey Expansion Fund

Genetic modeling of oncology drug response through CRISPR/enCas12a multiplexed perturbation platform

Precision oncology requires accurate mapping of genotype to phenotype to identify and deliver the specific and accurate therapy. Large-scale molecular profiling of tumors and genome-scale CRISPR/Cas9 knockout screens in cancer cell lines have provided revolutionary resources for cancer precision therapy and subsequent targeted drug development. However, CRISPR screens are often poor predictors of drug response, especially for “dirty” agents whose efficacy depends on targeting multiple members of a gene family (e.g. MEK inhibitor trametinib, a treatment for metastatic melanoma, targets both MAP2K1 and MAP2K2). To date, a technology that can be used to accurately model drug response by genetic perturbation is unavailable in human cells. Therefore, we propose to develop a highly multiplexed CRISPR perturbation screening platform to study clinically relevant genetic interactions rapidly and inexpensively. My hypothesis is to engineer the CRISPR/enCas12a system to target multiple genes simultaneously and provide an accurate genetic model of drug response and polypharmacology. My goal is to develop and utilize this polygenic perturbation platform to characterize the functional genomics of the FDA-approved oncology drug targets and discover novel synthetic vulnerabilities in drug-resistant tumors. This work will not only reveal how drug targets correlate with gene dependencies in complex cancer progression but provide a more accurate theoretical basis for cancer therapeutic intervention, and precision medicine. We are eager to employ this platform to develop combinatorial therapy options to benefit drug-resistant cancer patients.

Melanie K. Prodhomme, Ph.D.

Odyssey Fellow (2023-2026)
Department of Epigenetics and Molecular Carcinogenesis
Supported by: The Kimberly Clark Foundation

The regulation of DNA polymerase theta by ATM in non-small cell lung cancer

Cancer is characterized by uncontrolled growth and spread of abnormal cells following one or more mutational events. One of the main characteristics of tumor development is the acquisition of genomic instability leading to mutational events. This genomic instability can be partly attributed to inaccurate DNA damage repair. Several repair pathways can be used to repair DNA damage, but a recently discovered pathway, called Theta Mediated End Joining (TMEJ), has been found to have an important role during cancer development, given its strong mutagenic capacity. Overexpression of DNA polymerase theta (Polθ, encoded by the POLQ gene), a key enzyme in the TMEJ pathway, is found in many cancers. However, the function and the regulation of Polθ and TMEJ are still poorly understood. In recent years, TMEJ has been at the center of various studies, given its strong mutagenic ability but also for its synthetic lethality in BRCA1-deficient tumors, where Polθ is essential for their survival. Polθ has therefore become a new therapeutic target in many cancers. But BRCA1 deficient tumors are not the only ones that can benefit from synthetic lethality with Polθ. There are strong indications that ATM has a genetic interaction with Polθ. As Non-Small Cell Lung Cancer (NSCLC) tumors are reported to have epigenetic suppression of ATM (undetectable in ~ 40% of lung adenocarcinomas), this makes them a good model to study the close link between Polθ and ATM. Unfortunately, ATM's role in the regulation of Pol and TMEJ is not yet known.

My overall hypothesis is that ATM has the ability to regulate the level of Polθ protein, and therefore, regulates the TMEJ activity. Based on my preliminary data, ATM appears to affect post-translational degradation of Polθ. Therefore, the dual deletion of Polθ and ATM could result in synthetic lethality in NSCLC. This discovery could be of great help in the treatment of these tumors. In conclusion, this whole project will allow us to better understand the functioning of Polθ and TMEJ in the context of regulation by ATM, especially in lung cancer. Finally, we will be able to determine new biomarkers and signatures to guide patients towards a more appropriate therapy.

Cassandra Moyer, Ph.D.

Odyssey Fellow (2022-2025)
Department of Clinical Cancer Prevention 
Supported by: CFP Foundation

Targeting HER2-Positive Brain Metastases with a Novel Immunomodulatory Rexinoid

An estimated 40,000 women in the United States are living with HER2-positive metastatic breast cancer, for which there is no cure. Although there are several successful therapies for HER2-positive tumors, the challenge remains that most anti-HER2 drugs exhibit unwanted toxicity and treated tumors frequently develop resistance to therapy. There is a critical need for safe, effective therapies that can overcome anti-HER2 drug resistance and eliminate breast cancer metastases. A new drug, IRX, has been shown to activate the immune system and inhibit the growth of some cancers. More importantly, it is less toxic than current cancer therapies. Preliminary data from our lab shows that IRX can inhibit the growth of HER2-positive breast cancer, re-sensitize drug resistant cell lines to anti-HER2 therapy, and alter the activity of immune cells. We hypothesize that treatment with IRX can overcome anti-HER2 resistance and eradicate HER2-positive breast cancer metastases alone or in combination with current breast cancer treatments.
In this study, we will 1) show that IRX can inhibit tumor growth more when added to current anti-HER2 therapies, 2) identify key proteins, pathways and immune molecules by which IRX halts tumor growth, and 3) demonstrate how IRX can overcome anti-HER2 resistance to stop the growth of metastatic breast cancer. Overall, these preclinical studies will show that IRX can enhance the anti-cancer activity and reduce toxicity of current anti-HER2 therapies, will reveal how IRX inhibits tumor growth and its role on immune cells in the local tumor environment, and will demonstrate how IRX can be added to current therapies for the effective treatment of drug resistant tumors and HER2-positive breast cancer metastases, leading to the ultimate cure of metastatic breast cancer.

Pradeep Shrestha, Ph.D.

Odyssey Fellow (2022-2025)
Department of Pediatrics Research
Supported by: HEB Corporation

Modulation of the tumor immune microenvironment by targeting STAT3 and CD47-SIRPα axis for the treatment of osteosarcoma lung metastasis

Osteosarcoma (OS) is the most common malignant primary bone cancer frequent in children and young adults. Metastatic progression to the lungs and subsequent relapse is the leading cause of mortality in Osteosarcoma patients. Multiple chemotherapeutics as well as adaptive immune check-point inhibitors tested in clinical trials deemed ineffective without any significant clinical improvement. The lack of response to immunotherapy is secondary to an immunosuppressive tumor immune microenvironment (TME). OS-pulmonary metastases are significantly infiltrated by immune-suppressive cells that block the effector response against tumors. Modulating the TME therefore is a potential approach to promote anti-tumor immunity.
The primary goal of the study is to evaluate the immunotherapeutic strategy to mitigate OS-lung metastases by modulating TME. We will accomplish this aim by targeting signal transducer and activator of transcription 3 (STAT3) and innate immune checkpoint (CD47-SIRPα). STAT3 plays a central role in multiple oncogenic signaling pathways and is constitutively activated in multiple tumors including OS. Furthermore, STAT3 is also activated in diverse immune cells and modulates tumor-immune crosstalk leading to tumor induced immune-suppression. Consequently, STAT3 is potentially a valid and promising target for cancer immunotherapy. In addition, CD47-SIRPα axis is an innate immune checkpoint that regulates activation of innate immune cells. Tumor cells upregulate the expression of CD47 to evade anti-tumor immunity. Studies suggest that CD47-SIRPα blockade primes both anti-tumor innate and adaptive immunity. We anticipate that disruption of STAT3 pathway and neutralization of CD47-SIRPα axis will act in synergy to downregulate the immune-suppressive TME, promote activation and infiltration of anti-tumor immune cells resulting in a significantly less OS-lung metastasis burden.

Ailiang Zeng, Ph.D.

Odyssey Fellow (2022-2025)
Department of Cancer Biology 
Supported by: Theodore N. Law for Scientific Achievement

Roles of Microvesicles in Glioma Malignant Phenotype and TMZ Resistance

Glioblastoma (GBM) has an immunosuppressive tumor microenvironment enriched for myeloid-derived suppressor cells (MDSCs) as well as tumor-associated macrophages and microglia (TAMs). Selective targeting of TAMs has been tested as therapeutic strategy to relieve immunosuppression in GBM, yet no such therapies have yielded benefits in the clinic by far. Therefore, identification of novel therapeutics selectively reprogramming TAMs in combination with immune stimulating agents are urgently needed.
Debris of apoptotic tumor cells, which are enriched with large amounts of cellular lipids, including oxidized fatty acids and oxysterols, are constantly engulfed by the macrophage. The innovation in this work are to 1) develop a promising therapeutic target to restore macrophage/microglial phagocytosis and immunity and 2) combine macrophage/microglial lipid metabolism boosting with T cell immunity unleashing to revolutionize immune checkpoint blockade efficacy on GBM. Completion of our study will also lead to knowledge about mechanisms underlying anti-tumor immunity of macrophage/microglia and potentiate reprogramming the tumor microenvironment to increased immunogenic responses in GBM patients.