Current & Past Odyssey Fellows

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.

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.

Ronja Anugwom, Ph.D.

Odyssey Fellow (2018-2021)
Department of Experimental Radiation Oncology
Supported by:  Theodore N. Law for Scientific Achievement

Defining the H2AX-Independent DNA damage response pathway
A cell’s response to DNA damage is controlled by a network of signaling cascades that not only determine cell survival but also contribute to the maintenance of genomic integrity and tumor suppression. The current dogma is that a key DNA damage response factor, histone variant H2AX, is at the top of these signaling cascades. However, surprisingly DNA damage response still takes place even when H2AX is absent. In a previous study, we found that the MRE11/NBS1/RAD50 (MRN) complex is responsible for the recruitment of signaling and repair proteins in the absence of H2AX. Notably, downregulation of both H2AX and NBS1 led to impaired recruitment of downstream DNA damage response proteins. Moreover, the combined impairment of the H2AX- and NBS1-dependent DNA damage response pathways by CRISPR/Cas9 technology is lethal. This leads us to conclude that the DNA damage response signaling network involves redundant H2AX- and NBS1-dependent pathways.
The aim of this project is to investigate the poorly-understood H2AX-independent DNA damage response mechanism and the interplay between the H2AX- and NBS1-dependent pathways. We will characterize NBS1-dependent DNA damage signal transduction, investigate its influence on and its interaction with the H2AX-dependent pathway, and explore how these two pathways ensure downstream signaling, DNA repair, genome stability, cell cycle control, and cell survival. Dissecting the details within the complex DNA damage response network will not only clarify how cells survive after DNA damage but also reveal novel targets for cancer treatment. More specifically, this study will elucidate how redundant pathways operate and how synthetic lethality can be exploited in cancer treatment.

Youmna Atieh, Ph.D.

Odyssey Fellow (2018-2021)
Department of Genetics
Supported by:  Houston Endowment Inc. for Scientific Achievement

The Role of Basal Cell Extrusion in Cancer Mestastasis
During the progression of metastasis, cancer cells invade the underlying stroma towards the blood vessels. However, it is still unclear how cancer cells breach the basement membrane they lie on to escape their primary site. One emerging concept is that cancer cells reach the underlying tissue through a process called cell extrusion.
During homeostasis, extrusion is a process by which epithelial cells are removed to maintain optimal barrier function. Because cells are extruded apically into the lumen, they eventually die through loss of cell-cell contact or anoikis; however, oncogenic mutations shift cell extrusion basally, providing epithelial cells the possibility to override anoikis and invade within the stroma.
This project aims at identifying if basally extruded cells with upregulated survival signals could potentially initiate cancer invasion. Preliminary data indicate that cells can extrude both as single and collective clusters, however, it is still unknown which of the two modes is more favorable for survival and invasion. We will also test the hypothesis that oncogenic mutations in epithelial cells drive basal over apical extrusion in order to validate that basal extrusion is a mechanism used by cancer cells to invade underlying tissues. Finally, and as a longer-term project, we will evaluate how basally extruded cancer cells cooperate with immune cells after extrusion, and how this cooperation contributes to metastatic spreading.
Overall, we propose that basal cell extrusion provides a novel mechanism for cells to exit the epithelium and initiate invasion into the surrounding tissues.

Shu Zhang, Ph.D.

Odyssey Fellow (2018-2021)
Department of Cancer Imaging
Supported by:  Cockrell Foundation Award for Scientific Achievement

Development of Clinical CEST MRI Acquisition and Analysis Methods for Cancer Imaging

When we exercise, we “feel the burn” when our metabolically active muscles produce extra lactic acid. Aggressive tumors are also very active, and produce extra lactic acid using very similar metabolism. Therefore, measuring the acid level in tissues can aid in identifying aggressive tumors. Furthermore, therapies that slow tumor metabolism can decrease the acid level in tumors. Measuring the acid level soon after initiating treatment can be used to measure a very early response of the tumor to the treatment.
Our research program develops noninvasive imaging methods that measure the acid level in tumors. We use Chemical Exchange Saturation Transfer Magnetic Resonance Imaging (CEST MRI) to evaluate the rate that hydrogen atoms move between water molecules and other molecules in the body, such as proteins. High acid levels slow this movement of the hydrogen atoms, so that the movement rate can be used to measure the acid content in tumors. We have used our CEST MRI method to measure acid content in many small animal models of human cancers, and we have pioneered the measurement of acid content in cancer patients with our methods.
In this project, we will further improve our CEST MRI acquisition and analysis methods to be more useful in cancer imaging centers. We will expand our current imaging methods to evaluate large 3D tissue volumes to ensure that the entire tumor is evaluated. We will develop methods with very fast imaging speeds to improve patient comfort and clinical throughput. We have previously pioneered improvements that eliminate complications in CEST MRI caused by adipose tissue (fat), and we will incorporate these improvements in our new methods. We will further develop our image analyses that use data analytics and artificial intelligence methods, which are advanced techniques are viewed as future directions for medical imaging. To demonstrate our potentially broad impact on cancer imaging, our project will focus on glioblastoma, lung cancer and breast cancer. The goal of the glioblastoma study is to differentiate tumor recurrence that has high acid content from pseudoprogression caused by inflammation that has low acid content. The goal of the lung cancer study is to differentiate tumors with high acid content from lung infections that have low acid content. The goal of the breast cancer study is to differentiate acidic tumors from non-cancerous, non-acidic lesions. We anticipate tumor detection in these studies with > 90% specificity based on the large pH differences between tumors vs. non-cancerous lesions. As a longer-term goal, we plan to use CEST MRI to monitor the early response to therapies for many types of solid tumors.