Current & Past Odyssey Fellows

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.

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 Metastasis
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.

Didem Agac, Ph.D.

Odyssey Fellow (2020-2023)
Department of Immunology
Supported by:  HEB Corporation

The Role of Intratumoral Neurotransmitter Signaling in T Cell Exhaustion and Anti-tumor Responses

Immune checkpoint inhibition via CTLA-4, PD-1, and PD-L1 blocking has provided an effective and long-term durable cancer immunotherapy for many patients with diverse diseases, however, most patients do not respond to the therapy. This current limitation has sparked considerable interest in identifying novel checkpoints to elucidate additional inhibitory pathways.
Neurotransmitters (NTs) are small signaling molecules, generally secreted by neurons to facilitate the communication between these cells and their targets. NTs are detectable in serum and present in the tissue. Interestingly, immune cells (e.g. T cells, NK cells and macrophages) have been shown to produce NTs themselves. Immune cells also express receptors that enable them to respond to NTs in both tissue and circulation. The effects of NTs on immune cells have almost exclusively been immunosuppressive but, the role of NTs in the tumor microenvironment (TME) has not been studied. Finally, many classes of approved drugs target NTs, making these drugs potential repurposing candidates.
We have detected the presence of dopamine (DA) and norepinephrine (NE) in TME using a murine melanoma model. We have additionally identified that dopamine beta-hydroxylase (DBH, the enzyme that converts DA to NE) is expressed in a subset of human T cells in derived from melanoma tissue, using publicly available single-cell RNA-seq data. The T cells that express DBH also express high levels of exhaustion markers, raising the question of whether DBH high T cells can drive exhaustion. This proposal aims to study the role of DBH expressing cells in TME where we hypothesize that the conversion of DA to NE by Dbh high cells promotes a sustained level of NE to enhance immunosuppression, further promoting T cell exhaustion. We propose to overcome this suppression by utilizing FDA-approved adrenergic receptor blockers, as well as Dbh inhibitors. Ultimately, we propose that NT modulating agents can improve the efficacy of immune checkpoint inhibition.

Lawrence Bronk, Ph.D.

Odyssey Fellow (2020-2023)
Department of Radiation Oncology Research
Supported by:  Kimberly Clark Foundation

Uncovering the Cellular Mechanisms of Radiation Necrosis: The Role of Necroptosis

Radiation therapy is increasingly used in the treatment of both primary and metastatic brain cancers. Clinical studies have suggested a survival advantage associated with higher doses of radiation, but this trend has been associated with a higher incidence of radiation necrosis, a late term side effect. With no definitive cause and resulting in irreversible tissue damage, radiation necrosis is the most significant potential complication in the treatment of brain tumors. The incidence of necrosis is expected to climb with combined modality treatment and expansion in the use of immunotherapy. To date, there have been no reported cellular models of radiation necrosis, indicating that this toxicity is, in part, unable to be reproduced in simplified laboratory settings. In this project, we will develop and implement advanced organoid models that better recapitulate native brain tissue compared to 2D cultures. We will then examine the biological processes contributing to radiation necrosis using these models. In particular, we will investigate whether neurons are susceptible to necroptosis, a regulated form of necrosis, when exposed to radiation. Understanding the contributions of regulated cell death pathways following radiation to the brain could lead to targeted pharmacologic interventions for the early prevention or reversal of treatment induced sequelae. The amelioration of radiation necrosis may expand the therapeutic window of radiation therapy further enabling dose escalation and ultimately result in improved clinical outcomes.

Debabrata Das, Ph.D.

Odyssey Fellow (2020-2029)
Department of Genetics
Supported by:  Kimberly-Clark Foundation

KRAS/ERK-mediated regulation of RbAp46 and the epigenome
While cancer is largely considered as a genetic disorder, recent years highlight the contribution of global epigenetic abnormalities in mediating cancer progression. Mechanisms that mediate epigenetic changes range from histone modifications to DNA and RNA methylation patterns that alter the epigenome and the epi-transcriptome. However, mouse models with changes in epigenetic modulators only bear tumors in the context of oncogenic or tumor suppressor mutations, suggesting that changes in epigenetic modulators may synergize with oncogenic / tumor suppressor signaling. Despite the emerging role of epigenetic modulators in cancer progression a direct connection between oncogenic signaling and epigenetic remodelers has not been elucidated.
Oncogenic KRAS drives 30-90% of lung, colon, and pancreatic cancers, yet, clinical inhibitors of KRAS—and potential resistance mechanisms—remain elusive. KRAS relays signals primarily through a conserved kinase cascade that results in the phosphorylation and activation of extracellular-signal regulated kinases (ERK) which in turn regulates a variety of downstream substrates to execute different cellular responses, including proliferation, differentiation and survival. While inappropriate ERK activation appears causal to the development of multiple tissue-specific cancers, the molecules most directly involved in disease etiology are the substrates through which KRAS/ERK executes its orders. Thus, to obtain a clearer picture of the molecular basis of these diseases and to meet the critical need for novel therapeutic strategies, it is important to identify each of these ERK substrates and to dissect the genetic and molecular basis of their function in normal and diseased states.
The focus of this proposal is retinoblastoma-associated protein (RbAp46), a histone chaperone. We identified that RbAp46 is a substrate of KRAS/ERK signaling. This is exciting as it is the first direct link between epigenetic remodeling and KRAS/ERK signaling, in any system. The goal of this project is to dissect this relationship in vivo and determine the genetic and molecular mechanism that result in KRAS-mediated regulation of the epigenome.

Fernanda Grande-Kugeratski, Ph.D.

Odyssey Fellow (2020-2023)
Department of Cancer Biology
Supported by: Theodore N. Law for Scientific Achievement

Engineering exosomes to engage antitumor immune responses

Exosomes are membranous nanoparticles ranging from 40 to 150 nm in diameter released by cells into surrounding tissues and body fluids. They contain bioactive cargoes, such as nucleic acids, proteins, lipids and metabolites. Exosomes are key mediators of intercellular communication both locally and systemically. Due to their biocompatibility, long circulatory half-life and amenability to modification, exosomes have emerged as promising therapeutic vehicles. Our aim is to design exosomes able to engage immunostimulatory signals on T cells. For that, we engineered exosomes that present high surface levels of immunostimulatory proteins. We confirmed the enrichment of the proteins of interest at the surface of the engineered exosomes. Moreover, our preliminary findings show that the engineered nanoparticles enhance T cell activation, proliferation and cytokines production ex vivo and delay tumor growth in vivo. Our results suggest that exosomes can be exploited therapeutically to elicit antitumor immune responses and have translational potential for cancer treatment.

Arseniy Yuzhalin, Ph.D.

Odyssey Fellow (2020-2023)
Department of Molecular and Cellular Oncology 
Supported by: Theodore N. Law for Scientific Achievement

Inhibition of CDKS as a potential therapeutic strategy against breast cancer brain metastasis

Dr. Yuzhalin proposes to test the hypothesis that CDK5 activation promotes breast cancer brain metastasis by both facilitating cell adaptation/outgrowth in the brain and also by triggering mechanisms of immunosuppression. He suggests that existing, commercially available FDA-approved CDK5 inhibitors could become new therapeutics for patients with breast cancer brain metastases. The project’s specific aims are: (i) to determine brain metastasis-promoting functions of CDK5 in mouse spontaneous brain metastasis models and immunocompetent mouse experimental brain metastasis models; (ii) to explore deep mechanism of CDK5-enhanced brain metastasis; (iii) to evaluate the potential of targeting CDK5 for treatment of brain metastases in pre-clinical studies.