Current & Past Odyssey Fellows

Wei-Lei Yang, Ph.D.

Odyssey Fellow (2015-2018)
Departmentof Experimental Therapeutics
Supported by: Theodore N. Law Endowment for Scientific Achievement

The Evaluation of Autoantibodies against TP53 Mutant Proteins Serve as Biomarkers for Early Detection of Ovarian Cancer by a Novel Multiplex Immunoassay Analysis
Ovarian cancer is the leading cause of death among gynecological cancers. The overall cure rate of ovarian cancer is below 20% when detected at late stage. Detection of ovarian cancer in early stage could improve cancer mortality by 10-30%, but so far only 25% of cases are diagnosed in early stage. Detecting an autologous immune response to tumor-associated antigens (i.e., autoantibodies) might improve and allow early detection of cancer. TP53 tumor suppressor is a potential candidate as it is mutated and overexpressed in virtually all high grade serous ovarian cancers. Autoantibodies reactive to wild-typeTP53 have been reported in ovarian cancers at the time of conventional diagnosis. Numerous studies demonstrated the potential of autoantibodies being employed as the next generation of cancer biomarker. The goal of this project is to develop a multiplex micro-immunoassay analysis as a new platform to screen and evaluate whether autoantibodies against TP53 wild-type/mutant proteins may serve as reliable biomarkers for diagnosis and early detection of ovarian cancer. In addition, we will investigate the mechanisms of different immune responses for TP53 autoantibodies to specific TP53 mutation in ovarian cancer patients. We foresee that the quantitative assessment of TP53 autoantibody titers through our newly developed platform holds promise for earlier detection of ovarian cancer in combination with current ovarian cancer biomarker CA-125.

Spencer Wei, Ph.D.

Odyssey Fellow (2015-2018)
Department of Immunology
Supported by:  Anonymous Donor

Effect of oncogenic drivers on tumor immune responses
Immunotherapies can result in long-lasting durable responses across a broad range of tumor types, however, such remarkable responses are only achieved in a minority of patients. Tremendous clinical progress has been made in the field of cancer immunotherapy, particularly since the landmark FDA approval of Ipilimumab (anti-CTLA-4) for melanoma in 2011. This remarkable progress, however, has outpaced our understanding of the underlying biology of immune activation and host-tumor interactions. This project aims to expand our understanding of the mechanisms of immune checkpoint blockade therapies and furthermore, to investigate how properties of the tumor can affect sensitivity to these therapies.  In particular, this project focuses on understanding the cellular mechanisms of anti-CTLA-4 and anti-PD-1 checkpoint blockade, as well as investigation of fundamental mechanisms that regulate anti-tumor T cell responses.  Further mechanistic insights into these processes will be critical for the rational development of improved immunotherapeutic approaches, with the ultimate goal of extending extraordinary responses to more cancer patients.

Alejandro Tortoriello, M.D.

Odyssey Fellow (2016-2019)
Department of Faculty and Academic Affairs
Supported by:  Anonymous Donor

Bio-Innovation Program at MD Anderson Cancer Center
Bio-Innovation projects focus on the discovery, evaluation, and translation of technology for commercialization. Part of making cancer history is to reach as many people as possible. Great ideas need to leave the lab to impact people and create new opportunities. The primary focus of the fellowship is on the Innovation Corps (I-Corps) program and the Venture Mentoring Service (VMS) program. The I-Corps Program is now the premiere federally funded innovation and commercialization program in the U.S., with over 19 leading academic research institutions as regional partners.  This program was launched by the NSF, and adopted by the NIH, to provide training and assistance in translating technology and discoveries to the bedside. It is an initiative geared towards supporting Faculty and Trainees in the translation of their research technology and the improvement of federal funding success rates. Venture Mentoring Service (VMS) at Houston is based on MIT’s VMS program to help faculty members and students commercialize technology. VMS brings together world class mentors with academic ventures proving real life guidance in an effort to increase the success rates of commercializing technology. VMS will expand to all Texas through an initiative called Texas Venture Connect that will provide access to the mentor network to ventures from all 14 University of Texas institutions.

Di Zhao, Ph.D.

Odyssey Fellow (2016-2019)
Department of Cancer Biology
Supported by:  Theodore N. Law for Scientific Achievement

Synthetic Essentiality of Chromatin Remodeling Factor CHD1 in PTEN Deficient Cancer
Background: Prostate cancer (PCa) is the second leading cause of cancer death for men in the United States. Up to 70% of primary prostate tumors show loss of heterozygosity (LOH) at the PTEN locus, and loss of PTEN is a key initiation event in PCa development. Synthetic and collateral lethality have provided conceptual frameworks to identify cancer-specific vulnerabilities. Here, we explored an approach to identify potential synthetic lethal interactions through screening mutually exclusive deletion patterns in cancer genomes.

Methods: We sought to identify ‘synthetic essential’ genes, which might be occasionally deleted in some cancers but almost always retained in the context of a specific tumor suppressor deficiency, and posited that such synthetic essential genes would be therapeutic targets in cancers harboring specific tumor suppressor deficiencies.

Results: In addition to known synthetic lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic essential gene in PTEN-deleted cancers. In PTEN-deleted prostate and breast cancers, functional analysis showed that CHD1 depletion profoundly and specifically suppressed cell proliferation, survival and tumorigenic potential. Mechanistically, functional PTEN stimulates GSK3β-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via β-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in CHD1 protein stabilization, which in turn engages the H3K4me3 mark to activate transcription of the pro-tumorigenic TNFα/NF-κB gene network. In addition, we found CHD1 depletion significantly inhibits the progression of Pten-deficient prostate cancer genetic engineered mouse model.

Conclusions: Together, this study identifies CHD1 as a novel downstream effector in PTEN pathway, and verifies CHD1 as a novel therapeutic target in PTEN deficient prostate cancer and breast cancer. Additionally, this study provides a framework for the discovery of trackable targets in cancers harboring specific tumor suppressor deficiencies.

Ming Sun, Ph.D.

Odyssey Fellow (2016-2019)
Department of Bioinformatics and Computational Biology
Supported by:  Anonymous Donor

Decoding the Role of Long Noncoding RNAs in the Regulation of Glioblastoma Stem Cell
Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor. About twelve to fourteen thousand new cases of GBM are diagnosed in the United States each year.Despite the significant improvements in surgery procedure, chemo- and radiotherapy for GBM, the therapeutic benefit from these improvements remain limited. The median survival of GBM patients is around fifteen months and less than 10% of newly diagnosed GBM patients survive 5 years. Substantial evidence has revealed a sub-population of highly tumorigenic GBM cells, the glioblastoma stem cells (GSCs) that possess unique capability of self-renewal and differentiation into other cell types, persistent proliferation, and tumor initiation upon secondary transplantation. In addition to its critical role in tumor initiation, the GSCs confer therapeutic resistance of GBM in response to conventional chemo- and radiotherapy. Given the important role of GSCs in GBM pathogenesis, the elucidation of the molecular mechanisms that govern GSCs is thus essential to developing effective targeted therapeutics that eradicate the GSC population for treating GBM. Mounting evidence supports that long noncoding RNAs (lncRNAs) are a new class of RNAs that are critical for controlling the stemness of adult neural stem cells (NSCs) or gliomagenesis. The goal of this proposal is to systematically identify, and characterize the function and mechanism of these functional lncRNAs in GSCs.

Alexandre Reuben, Ph.D.

Odyssey Fellow (2017-2020)
Department of Surgical Oncology
Supported by:  Kimberley Clark Foundation for Scientific Achievement

Genomic instability drives immune and functional heterogeneity in synchronous melanoma metastases
Significant advances have been made in the treatment of metastatic melanoma in the form of targeted therapy and immune checkpoint blockade. However, the majority of patients do not exhibit durable responses to these forms of therapy. Our group previously identified genomic and immune biomarkers of response and resistance to checkpoint blockade. However, many stage IV patients are afflicted by multiple synchronous metastases, which further hampers therapeutic success. This can be appreciated by the heterogeneous therapeutic responses observed in more than 80% of patients. Genomic heterogeneity has been tied to mixed responses to targeted therapy, though this has not been studied in the context of immunotherapy. Furthermore, immune heterogeneity, as well as how it relates to genomic heterogeneity and to mixed responses has not been investigated. Our work aims to characterize the genomic and immune heterogeneity in patients with synchronous melanoma metastases treated with checkpoint blockade in order to overcome mixed responses to therapy.

Alicia Blessing-Bollu, Ph.D.

Odyssey Fellow (2017-2020)
Department of Experimental Therapeutics
Supported by:  CFP Foundation

Autophagic Ovarian Cancer Cells Exhibit Substantially Enhanced Sensitivity to Crizotinib
One of the major factors contributing to poor outcomes for patients with ovarian cancer is the persistence of dormant, drug resistant cancer cells after primary surgery and chemotherapy. Previous studies reported that the outgrowth of small, poorly vascularized nodules of dormant metastatic ovarian cancer cells found on the peritoneal surface at “second look” operations following primary surgery and chemotherapy occurs with a median of 16 months, but disease can recur after periods as long as 10 years. Consequently, the residual ovarian cancer cells remaining after surgery and chemotherapy are not growing exponentially and are considered dormant. Our laboratory has previously demonstrated that DIRAS3 (ARHI) is a master switch that induces both autophagy and tumor dormancy in human ovarian cancer xenografts and is upregulated in >80% of positive “second look” operations consistently associated with evidence of autophagy. Using a synthetic lethal siRNA screen, we identified several kinases that regulate growth and survival of ovarian cancer cells undergoing DIRAS3-induced autophagy; with the top three having already FDA-approved inhibitors. Thus, the central hypothesis is that DIRAS3 regulates tumor dormancy and induces autophagy and that dormant, autophagic cancer cells can then be selectively targeted by one of these inhibitors.

Daqian Xu, Ph.D.

Odyssey Fellow (2017-2020)
Department of Neuro-oncology - Research
Supported by:  Anonymous Donor

The Molecular Mechanism of PTEN-mediated PGK1 Dephosphorylation in Aerobic Glycolysis and Brain Tumorigenesis
Many cancer cells exhibit elevated glucose uptake and lactate production, regardless of oxygen availability. This phenomenon, known as aerobic glycolysis or the Warburg effect, facilitates tumor cell growth. PGK1, an instrumental ATP-generating enzyme in the glycolytic pathway, is often upregulated in cancer cells. By generation of ATP and 3-phosphoglycerate (3-PG), PGK1 plays an important role in coordinating energy production with one-carbon metabolism, serine biosynthesis, and cellular redox regulation. However, how PGK1 is posttranslationally regulated to promote glycolysis and tumorigenesis is largely unknown. Preliminary results indicated that the protein phosphatase activity of PTEN dephosphorylates and inhibits autophosphorylated phosphoglycerate kinase 1 (PGK1), which plays an important role in regulation of the Warburg effect. Consistently, loss of PTEN function resulted in PGK1 activation and enhanced aerobic glycolysis to promote tumor growth. Our continued study will elucidate the mechanisms underlying PTEN-regulated PGK1 autophosphorylation and determine the significance of this regulation in brain tumor development. Our study will highlight the dual roles of PGK1 as both a metabolic enzyme and a protein kinase in cell metabolism and an instrumental function of PTEN in regulation of a key metabolic enzyme in the glycolytic pathway. Thus, PGK1 might act as a unique molecular target for treating human brain tumors.

Yi Yang, Ph.D.

Odyssey Fellow (2017-2020)
Department of Molecular and Cellular Oncology
Supported by:  Anonymous Donor

Resistant Mechanism to PARP Inhibitors in Triple-negative Breast Cancers
Patients with triple-negative breast cancer (TNBC) have worse prognosis than the ones with hormone receptor–positive subtypes, effective treatment strategies for TNBC are urgently needed. Recently, our lab showed that c-Met mediates the phosphorylation of PARP at Y907, which results in PARPi resistance in triple-negative breast cancers (TNBC). We will further systematically validate the significance of c-Met-mediated phosphorylation in PARPi resistance in vitro and in vivo models and in TNBC patient samples. EGFR is another TNBC related RTK, we hypothesize that similar to c-Met, EGFR may also phosphorylate PARP but at a different site from Y907 which is phosphorylated by c-Met, resulting in increased activity and/or resistance to PARP. We will continue to determine the role of EGFR-mediated PARP phosphorylation in PARPi resistance in TNBC.