Current & Past Odyssey Fellows

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.

Pravesh Gupta, Ph.D.

Odyssey Fellow (2021-2024)
Department of Translational Molecular Pathology
Supported by: Cockrell Foundation for Scientific Achievement

Exploiting genetically engineered monocytes for neuro-immunotherapy of glioblastoma

Glioblastoma is a deadly brain tumor with a two-year survival rate of approximately 15%. Standard of care treatments comprising surgery, chemotherapy, and radiation therapies have failed to extend survival benefits beyond 18 months for these patients. Even extrapolation of immune-therapeutic modalities including checkpoint blockade and chimeric antigen receptor-based T -cell rejuvenating approaches have yet not significantly improved disease outcomes. This suggests to a limited understanding of myeloid cell dominated brain intrinsic immunity not only in healthy state but also inflamed glioblastoma microenvironment in contrast to T-cell skewed peripheral immunity. Hence generalization of T- cell therapies in glioblastoma could be a biased direction. Additionally, we noted a recurring school of thought suggesting myeloid cell-mediated immunosuppression in glioblastoma largely due to oversimplified interpretations from myeloid derived suppressor cells and M1/M2 confined macrophage functional states despite their enormous plasticity.
We challenged this dogma and performed an unbiased large-scale single-cell transcriptomics characterization of the glioblastoma immune contexture referenced to non-glioma brains and observed unprecedented heterogeneity and functional plasticity in myeloid cells comprising microglia, macrophages, monocyte-derived cells, and dendritic cells, which accounted for three-fourth of glioblastoma resident and infiltrating immune cells. We identified a deficit in brain centric neuroimmune signaling in glioblastoma immune microenvironment specifically on myeloid lineage cells, which was indicative of reduced tumor kill factors, enhanced- anti-inflammatory molecules and, -angiogenesis factors amongst many others that may contribute to tumor immune escape. Hence, we conceived a paradigm-shifting research “ODYSSEY” for the restoration of the neuroimmune axis by imparting multifunctional attributes to monocytes with key neuronal signaling molecules via novel lambda integrase mediated gene insertion platform. Our tailored strategy would potentially transform the immunosuppressive glioblastoma immune microenvironment to immune-activating and arrest tumor growth by enhancing innate immune functions. This will herald the onset of monocyte orchestrated neuroimmune cell-based therapies for glioblastoma.

Ching-Fei Li, Ph.D.

Odyssey Fellow (2021-2024)
Department of Molecular and Cellular Oncology 
Supported by: Houston Endowment for Scientific Achievement

Investigation of the role of BDKRB1 in PDAC progression and tumor microenvironment orchestration

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with features of early metastasis and extensive desmoplasia. The PDAC patient outcomes have not improved in decades, albeit a plenty of therapies that target PDAC have been tested but not successful. It could be due to most research focused on tumor cells only, whereas the effects of the stroma and immune cells during tumor progression have been largely ignored. Bradykinin receptor B1 (BDKRB1), plays a crucial role in the physiological process associated with coagulation, vasodilation and promotes inflammation and fibrotic diseases in pathological conditions. Based on the analyzed results of Cancer Genome Atlas (TCGA) database, BDKRB1 mRNA is upregulated in PDAC patients. BDKRB1 gene expression level positively correlates with poor survival in PDAC patients. To date, there is limited understanding on the role of BDKRB1 in PDAC. This proposal is aimed to discover and validate the impact of BDKRB1 in PDAC progression, and hopefully proves to be an effective treatment for PDAC by targeting BDKRB1.

Yuehui Zhao, Ph.D.

Odyssey Fellow (2021-2024)
Department of Genetics
Supported by: Theodore N. Law for Scientific Achievement

Delineating the tumor clonal evolution of therapeutic resistance and identifying clinical biomarkers in metastatic prostate cancer using single-cell sequencing and liquid biopsy genomics

Prostate cancer is the most commonly diagnosed cancer among men and a major cause of cancer-related deaths in the modern world. Metastatic prostate cancer is the most lethal form and has complex and heterogeneous patterns. With prostate-specific antigen (PSA) screening and Androgen Deprivation Therapy (ADT), the survival rates in patients with metastatic prostate cancer are prolonged. However, while many patients respond to ADT, some patients develop resistance and progress to the lethal disease: castration-resistant prostate cancer (CRPC). To improve the outcome of metastatic prostate cancer patients, a greater understanding of resistance is urgently needed. Additionally, PSA, the major biomarker for prostate cancer, cannot fully indicate the disease status. Thus, identifying other genetic markers beyond PSA is essential for monitoring the disease progression and response to treatment for personalized medicine.

The aim of this project is to delineate the tumor clonal evolution of metastasis and resistance to ADT in prostate cancer. We will profile the genomic changes in patient tissue biopsy samples at single cell level. We will also perform genomic analysis of circulating tumor DNA in patient blood plasma. The identified genomic alterations will be utilized to investigate the tumor heterogeneity. The therapeutic resistant clones will be detected and their clonal dynamics during the treatment period will be profiled. The genetic markers that indicate the treatment response are expected to be identified for outcome prediction, disease management, and treatment planning. We will also gain more insights into the mechanism of resistance to ADT. Besides, the single-cell data will be used to identify the metastatic clones. We expect to identify the mutations and copy number alterations associated with metastasis that can provide therapeutic targets for preventing or treating metastatic disease.