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Current & Past Recipients

Tracy W. Liu, PhD

Odyssey Fellow (2013-2016)
Department of Cancer Systems

Imaging single cell and their signaling cascades initiated during metastasis in vivo using window chamber models

It is now possible to image single cells, cell-cell interactions and molecular changes within a microenvironment using intravital imaging. However, intravital imaging techniques are invasive with small fields of views and limited applicability in relevant bone marrow sites, such as the spine and long bones, due to their thickness. Recently, femur and spinal chambers have been developed which allow for longitudinal studies (several months) of the bone marrow without any motor deficits or functional loss. The combination of intravital single cell imaging and bone window chamber models provides a dynamic imaging strategy that will begin to disentangle the complexity of metastasis in heterogeneous in vivo systems; for example, we can begin to identify molecular and structural changes that occur to create a favorable niche for metastases, signaling molecules that home metastatic cells to the bone and cell-cell interactions that promote metastatic formation. This strategy in concert with single cell isolation and genetic profiling may further identify relevant metastatic processes. Once established, this strategy may provide a means to identify novel metastatic targets and evaluate the effects of therapy potentially driving clinical translation.

Amanda Say, Ph.D. 

Odyssey Fellow (2013-2016)
Department of Experimental Radiation Oncology

Knock-in of low-molecular weight cyclin E into somatic cells and mice

Cyclin E is a key regulatory protein controlling the G1 to S phase transition in mammalian cells. In breast cancer, cyclin E is overexpressed and drives cells into the S phase more rapidly, resulting in increased proliferation. Cyclin E is processed at its amino-terminus by the serine protease elastase to generate LMWE isoforms of cyclin E that appear specifically in cancer cells. The LMW-E forms of cyclin E have an increased interaction with CDK2 and are resistant to CDK inhibitors. This enables the tumorigenic cells to bypass the G1/S phase checkpoint, resulting in increased tumorigenesis in both human mammary epithelial cells and in transgenic mouse models. To date, studies involving LMW-E tumorigenesis have relied mainly on the ectopic overexpression of LMW-E in cells with functional endogenous full-length cyclin E expressed in the background. These studies neglect to identify the direct contribution LMW-E provides to tumor formation as overexpression of full-length cyclin E alone does not result in tumorigenesis and could be obscuring the complete tumorigenic role of LMW-E in vivo. Preliminary studies support this idea as an increase cytoplasmic cyclin E, identified as LMW-E due to the loss of the nuclear localization sequence in the amino-terminus of LMW-E isoforms, correlates with an increase of poor prognosis in patients. This indicates full-length cyclin E expression maintains a level of stability in patients. The proposed plan is to generate both cell-line and mouse knock-in models of the LMW-E forms to examine the direct result of LMW-E expression in these model systems.

Hunain Alam, Ph.D.

Odyssey Fellow (2013-2016)
Department of Molecular & Cellular Oncology

Defining the Oncogenic Role of the Epigenetic Modifier KDM2A in Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related deaths in the United States, and as much as 85% of the newly diagnosed lung cancers are non-small-cell lung cancer (NSCLC). Despite great advance in the targeted therapy, mortality rate of lung cancer has not been significantly improved during the last three decades. Only 60% of affected individuals survive for five years mostly because of the neoplastic heterogeneity. Thus an identification of new druggable targets will pave an alternative way for the development of novel strategies to treat NSCLC. This project will study the tumor-promoting function of KDM2A in NSCLC. Based on preliminary results, the central hypothesis is that dysregulated KDM2A may repress tumor suppressor genes by altering H3K36 methylation profiles at their gene promoters and consequently promotes NSCLC. The proposed study will delineate the mechanism underlying the oncogenic role of KDM2A using genome-wide mapping approaches (e.g. chromatin immunoprecipitation sequencing) and genetic mouse models. The proposed study will also provide novel molecular insights into how dysregulation of an epigenetic modifier is coupled to NSCLC events and may prove useful in development of new therapeutic agents, such as small molecule inhibitors of KDM2A for NSCLC.

Yuhui Jiang, Ph.D.

Odyssey Fellow (2013-2016) 
Department of Neuro-Oncology

The mechanisms of PKM2-regulated cell cycle progression

Tumor-specific pyruvate kinase M2 (PKM2) is essential for the Warburg effect. Besides its well-established role in aerobic glycolysis, PKM2 directly regulates gene transcription and G1-S phase transition. However, whether PKM2 plalys a role in regulating other phases of cell cycle in unknown. Preliminary results show that PKM2 depletion blocked the association of Bub3/Bub1 SAC proteins to kinetochore and disrupted proper chromosome-to-spindle attachments leading to abnormal chromosome segregation in its kinase activity-dependent manner. This proposed study aims to elucidate the mechanisms underlying PKM2-regulated cell mitosis progression and examine the significance of this regulation in EGFR-promoted tumorigenesis. PKM2-phosphorylated Bub3 Tyr residues will be identified and the role of PKM2-dependent Bub3 Tyr phosphorylatin in regulation of Bub1 functions, the recruitment of Bub3/Bub1 and microtubules to kinetochore, and chromosome segregation will be examined. The effect of regulation of PKM2-dependent mitosis on EGFR-promoted tumor cell growth, cell cycle progression, transformation and glycolysis in cultured tumor cells and EGFR activation-promoted brain tumorigenesis in mice will also be examined. 

Junjie Li, Ph.D.

Odyssey Fellow (2013-2016)
Department of Cancer Systems Imaging

Dual Photothermal Ablation-Chemotherapy in Orthotopic and Subcutaneous Rat Models of Hepatocellular Carcinoma (HCC)

The incident of hepatocellular carcinoma (HCC) and death caused by HCC continue to rise in the United States. Though surgical resection and liver transplantation offers the hope for cure, few patients meet the criteria due to their existing intrinsic liver disease or a scarcity of donor liver. Conventional chemotherapy and radiotherapy have shown very little efficacy with inoperable HCC. New therapies that combine multimodality treatments are desperately needed to improve tumor response and prolong survival in patients with HCC. The focus of this research is on developing novel therapeutic strategies to enhance anti-tumor efficacy. The investigation of necrosis avid contrast agents (NACAs) constitutes potential strategies not only for detecting various diseases using MRI and Nuclear imaging, but also for developing therapeutic agents to target malignancies. Since most current cancer therapies may leave tumor residues left behind coupled with close-by necrosis, this study will sought to make necrosis as a single target common to all solid tumors, which can be easily achieved by using noninvasive vascular disrupting agent (VDA), minimally invasive radiofrequency ablation (RFA) or most other anticancer therapies.

Wanding Zhou, Ph.D.

Odyssey Fellow (2013-2016)
Department of Bioinformatics & Computational Biology

Quantitative analysis of tumor sequencing data

Tumorigenesis is typically accompanied by many waves of somatic mutations. Understanding these somatic mutations and their roles in cancer development requires not only the knowledge of what genes have mutated but also when and how much. This research tackles the problem of accurately measuring the fraction of mutated genes---the variant allele frequency---from Next Generation Sequencing data which is extracted from tumor samples. Automated, systematic and unbiased methods for such purpose are crucial to the downstream etiological analyses on which depends the promise of personalized cancer therapy. The work aims at both developing and implementing these methods to support scientific and clinical applications.

Xin-Jian Li, Ph.D.

Odyssey Fellow (2013-2015)
Department of Neuro-Oncology

Deciphering the role of phosphoglycerate kinase 1 in tumor development

Coordinating the regulation of glycolysis and tricarboxylic acid (TCA) cycle, a feature of tumor cells, plays a key role in cancer cell metabolism and proliferation. Understanding the precise cellular signaling regulating cell metabolism provides multiple potential therapeutic targets for cancer treatment. This study will elucidate the role of phosphoglycerate kinase 1 (PGK1), which catalyzes 1, 3-Bisphosphoglycerate to phosphoglycerate and generates ATP, in coordinating glycolysis and TCA cycle and tumorigenesis. Investigation of the regulations of PGK1 in response to growth factor and hypoxia stimulation and identify the effect of these regulations of PGK1 on glycolysis and TCA cycle, which in turn affect the tumor cell proliferation and tumor progression will be conducted. The proposed study will also identify novel functions of the key glycolytic enzyme PGK1 and may provide a molecular target for treatment of cancer.

Linda Odenthal-Hesse, Ph.D.

Odyssey Fellow (2013-2016)
Department of Molecular Carcinogenesis

Mechanism of mutagenesis and genome instability during the meiotic cell cycle

Changes in the genetic makeup of an individual, in the form of mutations and genomic rearrangements, are a common fingerprint of cancer cells as well as inherited diseases. This project will study the processes causing genome instability to increase the general understanding of cancer etiology. Intriguingly, genomes experience substantial instability during each meiotic cell cycle – much of which is induced by the repair of programmed DNA double-strand breaks by homologous recombination. Further, a significant proportion of an individual’s mutation burden can be attributed to de novo germ line point mutations. To date it is not known which proportion of these mutations arose as a consequence of recombination during meiosis, and which proportion arose prior to meiosis during stem cell proliferation. Using mouse meiosis as a model system, new molecular assays to definitively determine at high resolution the frequency and distribution of homologous recombination and point mutations during formation of sperm cells are being established. Several mouse mutants will be used to test current models to gain fundamental insights into the mechanisms of mutagenesis and genome instability. 

Youngbok Lee, Ph.D.

Odyssey Fellow (2013-2016)
Department of Cancer Systems Imaging

Real Time In Vivo Metabolic Profiling of Cancer Using Hyperpolarized Imaging Agents 

The goal of this research is to develop a new cancer diagnostic platform based on real-time in vivo metabolic imaging by Dynamic Nuclear Polarization (DNP), which capitalizes on the significant gains in sensitivity and selectivity. Magnetic Resonance Imaging (MRI) of hyperpolarized nuclear spins affords a signal enhancement of several orders of magnitude when compared to conventional MRI technique. Thus, the hyperpolarization techniques, in particular DNP, make a contribution to overcoming sensitivity and selectivity limitations of the typical MRI method through signal enhancements in their measurements, allowing the interrogation of  non-equilibrium processes including metabolisms in real time. Metabolism is fundamental to the cell and in cancer is significantly altered for cell proliferation and cell survival. Hyperpolarized metabolic imaging allows for anatomical and biological data to be determined concurrently. Using hyperpolarized pyruvate, succinate and glycine, which are biologically important metabolites in glycolysis, TCA cycle, and glycine metabolism, a new tool will be developed  for the early diagnosis of cancer as well as method in determining the aggressive profile of the disease. The focus will be on simultaneous monitoring of metabolic profiles and fluxes in the three metabolic cycles in cancer. A different in vivo metabolic profile should be seen in the more aggressive animal model. It is expected that the metabolic profiles and metabolic flux rates of hyperpolarized pyruvate, succinate, and glycine in vivo to substantially increase current understanding of metabolism in cancer. Ultimately, valuable predictors and biomarkers of neoplastic behavior may emerge.

Hao Hu, Ph.D.

Odyssey Fellow (2012-2015)
Department of Epidemiology

Uncovering the genetic bases for human diseases with sequencing data
Personal genome sequencing presents new challenges and opportunities for clinical interpretation of novel variants in human genomes. In response, new approaches for variant prioritization and disease-gene identification are emerging. Among the most promising of these are so called ‘burden tests’. In contrast to standard genome-wide association study (GWAS) approaches that evaluate the statistical significance of frequency differences for each variant in cases vs. controls, burden tests aggregate variants into discrete features—usually genes—to obtain greater statistical power. My major research interest is developing new burden test algorithms for finding disease-causing genes in humans, namely, the Variant Annotation, Analysis, and Search Tool (VAAST).  VAAST is aprobabilistic search tool that finds damaged genes and causal variants using whole-genome or exome sequencing data. Since the initial publication, we have repeatedly shown the utility of VAAST in both rare Mendelian diseases (e.g.Miller Syndrome and Ogden syndrome) and common, complex genetic diseases (e.g. breast cancer, Crohn diseases and hypertrilyceridemia), proving it is a robust software package that is highly accurate for both Mendelian and complex genetic diseases. Currently, we are incorporating support for family-based association study into the VAAST package (pVAAST), which makes uses of both case-control study design and pedigree sequencing data, achieving higher statistical power compared to transitional linkage analysis.

Nicholas Whiting, Ph.D.

Odyssey Fellow (2012-2015)
Department of Experimental Diagnostic Imaging

Improved Colorectal Diagnostic Imaging using Hyperpolarized, Functionalized Silicon Nanoparticles
There is an ever-growing need for accurate and effective colonoscopies to detect inflammation and abnormal growths in the lower gastrointestinal tract, such as polyps, diverticulosis, and cancer. The main objective of the proposed research is to develop a real-time molecular imaging nanoplatform to employ hyperpolarized silicon nanoparticles as viable molecular imaging agents for the early diagnosis of colorectal abnormalities and diseases, including cancer. The ability to non-invasively detect colorectal cancer is a huge step from traditional colonoscopies, and the increased detection sensitivity (and the absence of ionizing radiation) of hyperpolarized silicon nanoparticles is a huge improvement from typical MRI or CT scans. The increased resolution of this method will allow the detection of smaller polyps and lesions, as well as promote rapid feedback for decision making regarding patient selection, disease staging, and treatment monitoring; patients will benefit from a reduced incidence of invasive procedures, improved accuracy, and an increased ability to identify recurrences following treatment. The goal of this research is to form a new imaging method for detecting colorectal cancer at the earliest stages of development, thus dramatically increasing the patient's chances of successful treatment. The proposed research will systematically optimize the many components of this emerging field of colorectal cancer detection (including improvements to sensitivity, chemical specificity, and in vivo imaging), thus allowing it to quickly and efficiently translate from basic research to clinical imaging.

Francois Therriault-Proulx, Ph.D.

Odyssey Fellow (2012-2015)
Department of Radiation Physics

An in vivo plastic scintillation detector for ultrasound-guided seed implantation during low-dose-rate prostate brachytherapy
Plastic scintillation detectors (PSDs) have been shown to possess advantageous characteristics for in vivo dosimetry. Their sub-millimetric size, fast response (~ns), water-equivalence and independence with pressure and temperature are among the qualities of PSDs that other existing detectors do not have. In addition, the independence of their response to energies greater than 100 keV makes PSDs the ideal choice for the development of in vivo dosimeters for high-energy external beam radiation therapy. For irradiation modalities of lower energies, the energy-dependence of PSDs has limited their application. This is the case of LDR brachytherapy where radioactive sources of Iodine-125 (I-125) and Palladium-103 (Pd-103) are used, which possess polyenergetic emission spectra with average energies of 28 keV and 21 keV, respectively. The overall objective of this research project is to account for that energy-dependence and develop a clinically reliable PSD system that allows for accurate in vivo dosimetry during and after the implant of low-dose-rate (LDR) brachytherapy seeds.

Weiwei Yang, Ph.D.

Odyssey Fellow (2012-2015)
Department of Neuro-Oncology

The Mechanisms of PKM2-regulated Gene Expression
Tumor-specific pyruvate kinase M2 (PKM2) is essential for the Warburg effect. Besides its well-established role in aerobic glycolysis, PKM2 directly regulates gene transcription. However, the mechanism underlying this non-metabolic function of PKM2 remains elusive. This proposal aims to elucidate the mechanisms of PKM2-dependent histone H3 modification and examine the significance of this regulation in gene transcription and EGFR-promoted tumorigenesis. Overexpression or mutation of EGFR occurs in up to 60% of human glioblastoma. However, the efficacy of clinical treatment of some human cancers with EGFR inhibitors has been less significant than expected because of intrinsic and acquired resistance. Thus, the identification of novel key regulators for EGFR-regulated tumorigenesis may provide an alternative approach or combined approaches for treating EGFR-related glioblastoma.

Marc Ramirez, Ph.D.

Odyssey Fellow (2012-2015)
Department of Imaging Physics

Magnetic Resonance Imaging of Hyperpolarized 13C-Labeled Tracers and Their Metabolic Products: High-Throughput Technology for Preclinical and Translational Imaging Research
Developing safe and noninvasive imaging methods to accurately diagnose cancer and to rapidly evaluate response to therapy is challenging.  With its excellent soft-tissue contrast and high sensitivity to the abundant 1H nuclei in the body, magnetic resonance imaging (MRI) is well suited for high-resolution detection of morphological and functional changes in tumors.  However, metabolic imaging with traditional MRI methods is impractical. Recent advances in commercial technology to dramatically improve the MR signal of 13C-labeled tracers permit in vivo imaging of cancer metabolism. Preliminary results from preclinical and clinical trials are promising, yet engineering and economic challenges remain.  The hyperpolarized signal is short lived, and novel imaging methods to spatially, temporally, and spectrally separate the tracers from their metabolic products must be developed. Additionally, the cost per data point is remarkably high, requiring the consumption of a $15,000 per gram radical and requiring nearly an hour to prepare the tracer for a single animal acquisition.  The goal of this project is to promote the use of hyperpolarized MRI by developing high-throughput 13C imaging technology to reduce cost, improve statistical power, and lower experimental variance of preclinical cancer research, where imaging biomarkers can be established and ultimately be used to help guide patient-specific cancer therapies.

Hui Ling, Ph.D.

Odyssey Fellow (2012-2015)
Department of Experimental Therapeutics

The role of LONG1, a novel non-coding RNA located in 8q24 colon cancer risk locus, in Wnt signaling and chromosomal instability
In the 8q24 cancer risk region, it has been identified and cloned a novel long non-coding RNA transcript (LONG1, Long Oncogenic NcRNA Gene 1) that is highly over-expressed in microsatellite-stable (MSS) colorectal cancers (CRC), which have a poor prognosis. Functional studies showed that high LONG1 expression promoted tumor growth and metastasis, and exhibited resistance to chemotherapeutics drugs. In addition, exogenous LONG1 expression induced chromosomal instability (CIN) in HCT116, a near-diploid microsatellite-instable (MSI) CRC cell line with CIN-negative phenotype. Meanwhile, a consistent correlation between LONG1 and MYC expression both in cell line models and CRC patient samples were observed. However, LONG1-induced invasion and chemo-resistance cannot be rescued by reducing MYC expression, suggesting MYC is not the sole LONG1 target. Since MYC is one of the Wnt target genes, and higher β-catenin expression and higher Wnt activity in LONG1-overexpressing clones were observed, it is hypothesize that LONG1 may have a general activating effect on the Wnt signaling, and this enhanced Wnt signaling causes and maintains CIN  phenotype in the MSS type (the majority) of CRC.

Cecil Han, Ph.D.

Odyssey Fellow (2012-2015)
Department of Cancer Biology

Functions of a Novel RNA-binding Protein DBP-RB in microRNA processing
Defects in the DNA damage response (DDR) have been associated with various human diseases, including cancer. Emerging evidence suggests that microRNAs (miRNAs) play a key role in controlling the expression of genes involved in the initiation, activation and maintenance of the DDR. Recently, it has been shown that DNA damaging stress induces global changes in miRNAs expression. However, mechanism about how miRNA expression is regulated in response to DNA damage is largely unknown. Preliminary results showed that DBP-RB, one of RNA binding protein is interacted with both Drosha/DGCR8 and Dicer complexes, two primary miRNA processors. It has also been found that DBP-RB is colocalized with DNA damage foci and physically interacts with ATM (Ataxia Telangiectasia Mutated), a major signaling protein in the DDR. In particular, DBP-RB-depleted cells showed significant changes in the expression of a subset of miRNA and these DBP-RB-dependent miRNAs were also regulated in DNA damage-dependent manner. Based on the preliminary data, it is hypothesize that DBP-RB function as a mediator by transducing DNA damage signal to the miRNA processors to modulate miRNA processing by facilitating Drosha/DGCR8 and Dicer complexes. These proposed studies will be focused on understanding mechanisms by which DNA damage signaling is linked to miRNA biogenesis, providing valuable and mechanistic insights into the sensitivity and resistance of cancer cells to genotoxic drugs and a basis to establish novel therapeutic strategies.

Derrick Ong, Ph.D.

Odyssey Fellow (2012-2015)
Department of Genomic Medicine

Identification of factors that promote self-renewal of aged neural stem cells
Cytotoxic cancer therapy is associated with significant systemic toxicities across many organs, including the brain. As more cancer patients achieve long term survival benefit, these neurodegenerative sequelae are amplified and increase the susceptibility of patients to the neurodegenerative diseases including Alzheimer’s disease (AD). Advancing age itself is also a major driver of the neurodegenerative diseases and these conditions are fueled further by a greatly increased life expectancy worldwide. The impact of both cancer therapy and changing demographics, coupled with the lack of effective treatments for the neurodegenerative diseases, promises to extract a heavy social and economic toll worldwide, thus representing an urgent medical need. The aim of this project is to identify factors that promote self-renewal of aged neural stem cells. Interesting molecular targets will be identified and rigorously characterized with an eye on further drug development against these targets.  

Youting Sun, Ph.D.

Odyssey Fellow (2012-2015)
Department of Pathology

Systematic optimization of the next generation sequencing pipeline for cancer research
The goal of the project is to optimize the next generation sequencing (NGS) pipeline in order to facilitate biomarker discovery and key regulatory network identification in cancer biology. Currently, much of the complicated work flow of NGS remains as a black box to researchers. However by systematic modeling and simulation, key factors that affect sequence coverage, signal detection, and results accuracy will be revealed, which will shed light on NGS experiment design. In addition, better understanding of the workflow may lead to the development of more effective feature extraction methods, which in turn render better sensitivity and specificity in biomarker discovery. A second project is to detect signature patterns of genomic/epigenetic changes associated with tumor subtypes, recurrence, response to therapy, and survival. To this end, integrative multidimensional data analysis will be performed. Data sources include genomic, epigenetic, proteomic, and clinical data.

Sudha Krishnamurthy, Ph.D.

Odyssey Fellow (2012-2015)
Department of Head and Neck Surgery

Tumor Initiating Cells and Genomic alterations in Head and Neck Cancers
Head and neck squamous cell carcinoma (HNSCC) causes significant morbidity and mortality in the United States and worldwide, with over 250,000 diagnoses and 125,000 deaths annually. Despite the various advancements in treatment modalities, the 5 year survival rate is only 20-30% in advanced head and neck squamous cell carcinomas. This has been mainly attributed to the increased rates of recurrences and distant metastasis, the processes of which are poorly understood. Cancer stem cells (CSC), also known as tumor initiating cells, are believed to be the drivers of tumor recurrences and metastatic spread with its properties of chemo-radio resistance, and epithelial to mesenchymal transition.  The main goal of this project is to understand, and develop better CSC models to examine response to existing anti-cancer treatment, and to define new therapeutic targets. Specifically it hopes to understand how the genomic alterations and mutations identified in oral cancer affects the behavior and maintenance of oral cancer stem cells, including their capacity to avoid differentiation, apoptosis, and senescence.

Tyler Moss, Ph.D.

Odyssey Fellow (2012-2015)
Department of Systems Biology

MicroRNA Regulation of Signaling Networks Important in Cancer  
The focus of this project is on understanding the role of miRNA on signaling networks in cancer cells and to identify miRNA that can be utilized as therapy in combination with FDA approved chemotherapy. Screening of 879 miRNA coupled to phospho proteomics using 170 antibodies, and RPPA platform in three different breast and ovarian cancer cell lines have been completed. From these screening, it has been identified that 155 miRNA are significant in their modulation of signaling. Tyler will study a sub-set of these miRNA by using a systems approach combining computational modeling of miRNA effect on networks, bioinformatics mining of patient data from the TCGA and biochemistry and experimental biology. A second project that Tyler will work on is to integrate cellular automata models of cell-cell interaction with co-culture single cell analysis of cancer cells and fibroblasts to understand the role of signaling networks in modulating interactions with the microenvironment. These studies are based on clinical data with collaborators in Gynecologic Oncology and specific WNT signaling components has been identified as being upregulated in ovarian cancer cells in their interactions with fibroblasts.

Hoon Kim, Ph.D.

Odyssey Fellow (2011-2014)
Department of Bioinformatics & Computational Biology

Integrated Genomic Analysis of Regulatory Networks in Ovarian Cancer Subtypes 
The underlying vision of this research is to enhance the understanding of biological mechanisms governing cancer. Network analysis on high-throughput cancer data for this purpose will be performed. These studies may identify master regulators that can be therapeutically targeted. Barriers to achievement of network-level analysis of cancer can be the effect of tumor infiltrating normal cells and the lack of systematic network analysis integrating multiple types of high-throughput cancer data. To address these issues, the study will focus on high grade serious ovarian carcinomas (HGSC) while extension to other cancers is possible once appropriate data are available for analysis. Successful realization of the study will help to identify the gene regulatory networks responsible for molecular pathogenesis of tumors cell in HGSC, and will provide clues for biological mechanisms of non-tumor cell infiltration present in some tumors while not in others and will lead to potential applications in the prevention and treatment of ovarian cancer. 

Bo Zhong, Ph.D.

Odyssey Fellow (2011-2014)
Department of Immunology

Regulation of TLR- and TCR-Mediated Signaling by Ubiquitin-Specific Protease 25
This project investigates how TCR signaling and T cell differentiation are regulated by ubiquitination and deubiquitination process and how dysregulation of this process leads to autoimmune diseases and tumorigenesis. Although there are several reports indicating the link between ubiquitination defect and tumorigenesis, the exact mechanisms are poorly understood. USP25 as a negative regulator for both TLR- and TCR-mediated signaling has been identified. With autoimmune disease models and tumorigenesis models established, the plan is to elucidate the mechanisms by which USP25 regulates TLR and TCR signaling and investigate whether and how dysregulation of USP25-mediated deubiquitination regulates tumorigenesis. This study will further the understanding of how TLR- and TCR-mediated signaling is finely tuned by ubiquitination and deubiquitination and how deubiquitination-mediated dysregulation of TLR and TCR signaling leads to tumorigenesis.

Richard Bouchard, Ph.D.

Odyssey Fellow (2011-2014)
Department of Imaging Physics

Combined Photoacoustic-Ultrasonic Transrectal Imaging of Prostate Brachytherapy Seeds

Photoacoustic (PA) imaging is a new imaging technique in which tissue is irradiated with nanosecond pulses of low-energy laser light. Through the processes of optical absorption followed by thermoelastic expansion, broadband ultrasonic (US) acoustic waves can then be detected and spatially resolved to provide an image that is related to the local optical absorption of tissue constituents. Generally, PA imaging cannot offer the soft tissue contrast afforded by US imaging. However, using an ultrasound transducer in PA imaging it is possible to obtain coregistered PA and US images. Due to the increased optical absorption of metal (when compared to soft tissue), PA imaging has already been demonstrated to improve image contrast of 21- and 30-gauge needles in excised tissue specimens. Consequently, a combined PA and US (PAUS) imaging approach will not only improve needle visualization during a seed implantation procedure, but also promises to allow for the reliable visualization of the (conventional, non-modified) seeds themselves. Such a capability would improve adherence to a patient's dosimetric treatment plan, may allow for an adaptive treatment plan during the procedure itself, and could obviate the need for costly and ionizing CT-based post-implant evaluations.  

Da Yang, Ph.D.

Odyssey Fellow (2011-2014)
Department of Pathology

Defects in microRNA biogenesis: a new hallmark of colorectal cancer

Colorectal cancer (CRC) remains one of the major causes of cancer deaths in the United States. Prevention and detection in its early stages as well as monitoring disease progression and predicting therapy outcome are hindered by suboptimal compliance with strategies. Identification of biomarkers for detection and prognosis and candidates for therapeutic intervention is a significant area of CRC investigation. MicroRNA (miRNA) is ∼22nt small non-coding RNA that plays a pivotal role in multiple cellular processes by inhibiting mRNA translation. MiRNAs are closely involved in tumorigenesis through either suppressing tumor by targeting oncogenes (e.g. miR-15a targeting BCL2) or promoting tumor by targeting tumor suppressors (e.g. miR-21 targeting PTEN and miR-17-92 cluster targeting E2F1). Recently, accumulating evidence has indicated that aberrant expression of miRNAs is associated with colorectal cancer development and progression. These discoveries are poised to lead to novel targets or tools for colorectal cancer therapeutics. Moreover, given miRNAs could be secreted by tumor into plasma, where they are stably protected from RNases, miRNAs that are dysregulated in tumor have a great potential as non-invasive cancer biomarkers. In this regards, the elucidation of the cause and consequence of miRNA dysregulation in CRC will help better understand the pathogenesis of colorectal cancer and discover novel molecular targets for the development of prognosis biomarkers and anticancer therapeutics.

Lara Kingeter, Ph.D.

Odyssey Fellow (2010-2013)
Department of Molecular and Cellular Oncology

Evaluating the contribution of Mincle signaling in chemotherapy-induced mucositis
Mucositis is a condition caused by chemotherapy-induced damage to the mucosal tissues of the alimentary tract. It is one of the most common side effects of chemotherapy or radiation treatment, and occurs in 40-100% of cancer patients undergoing chemotherapy. Mucositis symptoms can be incapacitating, and include mouth and throat soreness, nausea, vomiting, diarrhea, and ulceration of the mucosal membranes of the alimentary tract. Patients may require extensive supportive care and hospitalization, which substantially increases their cost of treatment. In addition, patients suffering from mucositis may need to interrupt chemotherapy or radiation treatments until symptoms resolve, which can have negative consequences for their clinical outcome. The transcription factor NF-κB has been implicated in mucositis, as many of the cytokines, chemokines, and other inflammatory mediators involved in mucositis progression are regulated by this key transcription factor. This project will: determine the in vivo significance of Card9 signaling to NF-κB in chemotherapy-induced mucositis; identify Card9 binding partners involved in Mincle signal transduction and will evaluate the role of Mincle in the development of mucositis following chemotherapy.

Yun Zhang, Ph.D.

Odyssey Fellow (2010-2013)
Department of Genetics

A mouse model of sporadic breast tumors with a conditional p53 mutation
Missense mutations in the tumor suppressor gene p53 are present in more than 50% of human tumors. In particular, the arginine-to-histidine mutation at codon 175 (p53 R175H) has been found in more than 4% of human breast cancers. p53 mutations fall into two general categories: germline mutations that are associated with hereditary tumors, and somatic mutations that can cause sporadic turmors. Mouse models for cancers induced by p53 germline mutations have been established and characterized. However, hitherto there are no accurate animal models for sporadic tumors induced by p53 somatic missense mutation, although this mechanism of inactivating p53 occurs in a large fraction of human cancers. The project proposes to generate mouse models for sporadic breast cancer that can be induced by a conditional p53 R175H  mutation (corresponding to R175H in humans) specifically in mammary tissues. Experiments include generating engineered mice carrying a conditional p53 R175H  mutation; monitoring breast tumor formation following sporadic expression of p53R172H and investigating the molecular mechanisms of tumor development.

Xindong Liu, Ph.D.

Odyssey Fellow (2010-2013)
Department of Immunology

The Molecular Control of T-cell Tolerance
T-cell tolerance represents a negative regulatory mechanism to maintain T cell hyporesponsive to self tissues which minimizes the risk of autoimmunity. Importantly, induction of T-cell tolerance is hijacked by tumors in dampening the T cell anti-tumor function, which leads to tumor evasion. In addition to T cell receptor (TCR), accessory costimulatory receptors on T cells, such as CD28 and ICOS, play important roles in productive T-cell activation. It was found that in the absence of positive costimulation (both CD28 and ICOS signaling), activation of T cells by TCR signal alone results in their tolerance, similar to in vivo-rendered T-cell tolerance. The induction of T-cell tolerance is accompanied by selective activation of genes (Grail and Cbl-b) that inhibits TCR signaling as well as repression of T-cell cytokine genes (such as IFN-γ and IL-4). This in vitro T-cell tolerance induction model is a powerful and physiological system that would enable large quantities of tolerant T-cell to be generated, characterize the molecular control of their gene expression and study the stability or plasticity of T-cell telerance program. The project proposes to elucidate the molecular mechanism that controls T-cell tolerance program. Through the analysis of gene expression profiles and epigenetic modifications in tolerant T cells together with immunological analysis of tolerant T cell behavior in vivo, the aim is to identify key factors that control T-cell tolerance induction and maintenance. This project has broad therapeutic implications in cancers and autoimmune diseases. 

Prabodh Kapoor, Ph.D.

Odyssey Fellow (2010-2013)
Department of Carcinogenesis

Mechanisms of the INO80 Chromatin Remodeling Complex
The structure of chromatin has profound influence on nuclear functions, such as transcription, DNA replication, recombination and repair. Disruptions of these functions can lead to defects in gene expression and DNA damage repair, which constitute major underlying causes of many human cancers. Recent findings indicate that eukaryotic cells utilize two major classes of enzyme complexes to modify chromatin structure. These multi-protein complexes alter nucleosome architecture, either by covalent modifications of the histones (such as the histone acetyltransferases, HATs), or by ATP-dependent perturbations of histone-DNA interactions (the SWI/SNF family of complexes). Recent studies have shown that the INO80 complex is involved in multiple fundamental biological processes, such as in DSB repair and checkpoint regulation. The involvement of a single complex in different functions necessitates distinct regulatory mechanisms. Despite progress in linking chromatin remodeling to multiple processes involved in genome maintenance, mechanistic understanding of these links is currently lacking. As such, it is critical to reveal the biochemical and structural mechanisms of the INO80 complex underlying its activities in distinct biological processes.

Sofie Claerhout, Ph.D.

Odyssey Fellow (2009-2012)
Department of Systems Biology

Tumor dormancy and autophagy: implications for breast cancer
Recurrent metastatic disease is a major clinical problem among breast cancer patients, resulting in high morbidity and mortality. Hormone receptor positive (estrogen receptor, ER+) breast cancers can enter a prolonged period of dormancy resulting in recurrence 10-20 years later. Indeed, the long term outcome for patients with ER positive breast cancers is almost as bad as for those with ER negative cancers. In the case of late recurrence, cells that escape the initial therapy survive in a dormant state and ‘hide’ for years or decades ultimately giving rise to incurable metastases. Recent collaborative studies have suggested that autophagy, known as a survival mechanism in many cancers including breast cancer, may be required for tumor dormancy in ovarian cancer. The molecular mechanisms of cancer dormancy that allow cells to enter a dormant phase, escape from therapy, ‘reawaken’ and become occult after many years of dormancy are poorly understood. Moreover, one of the biggest problems that have hampered this field is the lack of defined molecular markers. Therefore, this project aims to investigate the genes involved in breast cancer dormancy and to examine whether autophagy can render breast cancer cells dormant and indolent for a long time period, only to awake with lethal consequences.

Calley Hirsch, Ph.D.

Odyssey Fellow (2009-2011)
Department of Biochemistry and Molecular Biology

The role of Gcn5 in mouse embryonic stem cells
Gcn5 is a histone acetyltransferase (HAT) enzyme associated with gene activation and is required for mammalian development. Furthermore, Gcn5 has been linked to a subset of pediatric tumors and is a known co-activator of c-myc and the p53 tumor suppressor protein. However, few Gcn5 target genes have been identified in mammalian cells. Preliminary data suggests that Gcn5 either directly or indirectly regulates the expression of a subset of ES cell markers and epigenetic regulatory genes. The proposal will build on these observations to gain a better understanding of Gcn5 function in mammalian development by: 1. Identify Gcn5 target genes and Gcn5-dependent epigenetic modifications in mouse ES cells and 2. Determine the role of Gcn5 in reprogramming of mouse embryonic fibroblasts (MEFs) to induced pluripotent stem (iPS) cells.

Marites Melancon, Ph.D.

Odyssey Fellow (2009-2012)
Department of Imaging Physics

Targeted Nanoshell-Based Agents for MRI-Guided Thermal Ablation of Head and Neck Cancer
In patients with advanced head and neck cancer (HNC), local tumor progression is the main cause of cancer-induced morbidity and mortality. Among patients with HNC treated with aggressive local-regional therapy, the local-regional recurrence rate is approximately 50%. In patients with local-regional recurrence, further surgery or radiotherapy is often not feasible owing to limited normal tissue tolerance. Thus, there is a need for innovative noninvasive or minimally invasive techniques that target recurrent HNC while exerting minimal effects on normal tissue. Among the techniques being investigated, thermal ablation is one of the promising options. However, thermal ablation for HNC currently has a major limitation: heat is delivered not only to tumor but also to surrounding normal tissues, which means that thermal ablation for treatment of lesions proximal to vital blood vessels and neural structures is associated with a substantial potential for life-threatening complications. If this limitation is to be overcome, thermal ablation will need to be modified such that heat is preferentially delivered to tumor and normal tissues are spared.

Abhinav Jain, Ph.D.

Odyssey Fellow (2008 - 2011)
Department of Biochemistry and Molecular Biology

p53: A key transcriptional regulator in human embryonic stem cells
The remarkable ability of embryonic stem cells (ES) to self renew and differentiate into a wide variety of cell types gives them incredible potential for use in drug development and regenerative therapy. A ‘trinity’ of nuclear regulators, Oct4, nanog and Sox2, governs pluripotency in vivo and in vitro. The molecular events that take place during self-renewal and differentiation of mouse ES (mES) cells are fairly well defined. In pluripotent mES cells, tumor suppressor p53 is highly expressed but restricted to cytoplasm, suggesting regulated inhibition of p53 functions. Retinoic acid (RA) promotes ES cell differentiation and loss of pluripotency. During RA-induced differentiation, p53 directly represses the pluripotency factor, nanog. Other roles of p53 in differentiation of ES cells are less clear. Compared to mES cells, understanding of transcription regulation in human ES (hES) cells is insignificant. p53 is expressed at very low levels in hES cells, compared to mES cells, indicating different mechanisms regulate p53 levels, which are increased during RA-induced differentiation in hES cells. Based on the available evidence and preliminary data, I hypothesize that mechanisms that induce loss of pluripotency also activate p53 in hES cells. Activated p53, in association with specific partner proteins, binds to target genes and effects chromatin modification to regulate target gene expression, reinforcing loss of pluripotency. In the future hES cells will be used as a tool to treat deadly diseases, e.g., cancer, and degenerative diseases, e.g., Parkinson’s. Therefore, a better understanding of transcriptional regulatory networks in these cells is necessary.

Yung Carmen Lam, Ph.D.

Odyssey Fellow (2008 - 2011)
Department of Molecular & Cellular Oncology

Understanding the role of Apollo on telomere protection and maintenance
Proper telomere maintenance is critical for cellular survival. Telomere dysfunction results in genomic instability, manifested as DNA breaks and resultant chromosomal fusions. In the absence of intact p53/pRb dependent checkpoints, this level of genomic instability is potentially cancer promoting. Apollo is a newly discovered telomere interacting protein of as yet unknown function. Our recent observation linking telomere dysfunction to the onset of genomic instability in cells derived from our Apollo knockout mouse indicates that the Apollo null mouse provides a unique genetic platform to explore the molecular mechanisms by which telomere uncapping contributes to cancer. We propose to test the following hypothesis: Loss of Apollo leads to telomere dysfunction and activation of a DNA damage response (DDR) at telomeres to initiate cellular senescence. In the absence of p53, the increased genomic instability promotes tumor initiation and progression.

Rachel Miller, Ph.D.

Odyssey Fellow (2008 - 2011)
Department of Biochemistry and Molecular Biology

Non-Canonical Wnt-4 Signals in Kidney Tubulogenesis
The pronephros of Xenopus laevis (frog) is composed of a single nephron. This morphologic simplification in combination with additional relevant attributes provides us with an excellent model of the vertebrate kidney. In this proposal, I will outline strategies to study the contribution of non-canonical Wnt signals to the process of kidney tubulogenesis. Wnt signals contribute in diverse manners to most normal developmental processes. Importantly, they further act in the pathological progression of multiple human cancers, including those of the kidney. Extracellular Wnt ligands have the capacity to activate "canonical" (β-catenin/ Lef/ Tcf-mediated) and/or "non-canonical" (small GTPase or calcium-mediated) intracellular pathways. Wnt-4, which has been shown to play a crucial role in vertebrate kidney tubulogenesis, potentially activates both canonical and non-canonical signaling pathways. While our work and that of others has recently shown a requirement for canonical/ β-catenin signals in nephric development, the likely contribution of non-canonical signals to kidney formation (or cancer) has not been studied. The proposed research is novel in assessing non-canonical Wnt pathway contributions to kidney tubulogenesis in vivo, and in applying the experimental advantages of amphibians. Further, although my immediate study is centered upon kidney, our findings are predicted to be relevant to the formation (or the pathologic progress) of other tubulogenic tissues such as lung, breast, prostate and pancreas - potentially providing for a larger generality.

Grace Smith, M.D., Ph.D.

Odyssey Fellow (2008 - 2010)
Department of Radiation Oncology

Patterns of Care and Disparities in the Treatment of Early Breast Cancer
Quality assessment of cancer care has emerged as a national priority. Evidence suggests that breast cancer treatment patterns are not uniform, and certain disadvantaged patients receive suboptimal care. Yet prior studies have limited patient representation, and the true magnitude of patients receiving suboptimal care is unknown. As no nationally representative studies of breast cancer treatment rates exist, patterns of care in the U. S. have not been fully characterized. Accordingly, we seek to identify regional disparities in the care of early stage invasive breast cancer; identify potential explanatory factors contributing to disparities; and assess the impact of disparities on breast cancer outcomes and associated costs using a novel, nationally representative, comprehensive cohort of older breast cancer patients. We hypothesize that there is significant variation in breast cancer treatment across the nation, and that patients who have suboptimal treatment also experience worse breast cancer morbidity, mortality and costs of care. Quantifying the association between treatment barriers and breast cancer morbidity and mortality will: 1) provide a novel understanding of treatment disparities in regions of the United States that have been largely neglected to date, 2) promote the key identifiable factors associated with high quality care and favorable breast cancer outcomes and 3) provide an original contribution to the scientific community by validating the novel methodology of using claims data in breast cancer research. Therefore, expected results from our research have the potential to directly impact the treatment and secondary prevention of breast cancer morbidity and mortality in more than 200,000 women per year diagnosed with breast cancer, but will particularly impact disadvantaged patients experiencing barriers to high-quality care. Recognizing the most vulnerable patients at the highest risk for barriers to treatment, adverse events and increased cost burdens is a key step toward improving cancer outcomes in neglected patient populations.

Jae Ho Cheong, Ph.D.

Odyssey Fellow (2007 - 2009)
Department of Molecular Therapeutics (Systems Biology)

Metabolic Stress and Cancer Cell Biology
Uncontrolled cancer cell proliferation requires both oncogenic aberrant growth signals and sufficient cellular bioenergetics. PI3K-AKT-mTOR signaling pathway is a well-known principal cellular growth signaling pathway and its aberrant activation is reported across many cancer types. The LKB1-AMPK pathway, a major cellular energy sensing and regulation machinery, has a cross-talk with PI3K-AKT-mTOR pathway, consolidating the emerging intimate relationship between physiological control of energy metabolism and cancer growth. Thus, targeting cancer bioenergetics regulatory pathway LKB1-AMPK and a major aberrant growth signaling pathway PI3K-AKT-mTOR will create unique opportunity for such combined targeted therapies from two distinct but interrelated aspects by focusing on the 'pathognomic' biologic derangement of cancer - unlimited growth and proliferation. The implication of our proposal will be relevant to the general understanding of cancer energy metabolism regulation and should provide insights how to further exploit the concept of deranged cancer bioenergetics and aberrant growth signals to achieve more effective and selective strategies for cancer patients.

Renee Chosed, Ph.D.

Odyssey Fellow (2007 - 2009)
Department of Biochemistry & Molecular Biology

Regulation of Mitosis by the Set1 Methyltransferase
Recently, members of the Dent lab demonstrated that phosphorylation of serines in one yeast kinetochore protein, Dam1, by the kinase Ipl1 was inhibited by the methylation of an adjacent lysine by the Set1 methyltransferase. Prior to this study, histone H3 lysine 4 was the only known substrate methylated by Set1. I hypothesize that Set1 has additional non-histone substrates and that methylation by Set1 on kinetochore-associated proteins may play a role in ensuring proper chromosome segregation. I will use biochemical techniques to identify non-histone substrates of Set1 and use yeast genetics to understand the consequences of Set1 methylation of the substrates in vivo. In the long term, demonstration that cross-regulation between methylation and phosphorylation on kinetochore proteins affects the progression of normal chromosome segregation may allow for identification of new targets for cancer therapies.

Sean Hartig, Ph.D.

Odyssey Fellow (2007 - 2009)
Department of Pediatrics Research

'Outside-In' and 'Inside-Out' Signaling Mechanisms for Endocytosis of EGF and FGF Receptors
Overexpression or activating mutations of the receptor tyrosine kinases (RTK) occur in solid tumors, including bladder, breast, colon, ovarian, prostate, renal and squamous cell carcinoma. After binding with their cognate ligands, the receptors trigger a similar complement of intracellular signaling molecules leading to their internalization through endocytosis. CIP4, a cytoskeletal protein discovered in the Corey lab, recruits proteins to the plasma membrane, leading to actin-mediated remodeling and receptor internalization. I hypothesize that CIP4 contributes differentially to RTK endocytosis and through advanced optical imaging, specific components including CIP4, will be studied to determine how RTK endocytosis is perturbed in cancer cells for translation into new therapeutic strategies.

James Jackson, Ph.D.

Odyssey Scholar (2007 - 2009)
Department of Cancer Genetics

Role of p53 point mutants in mammary tumorigenesis and drug response
p53 is a tumor suppressor gene that can direct damaged and potentially cancerous cells to growth arrest or cell death, and thus its inactivation is required for the majority of cancers to develop. Mouse models of p53 null alleles or point mutants develop lymphomas and sarcomas, not epithelial cancers, such as breast, colon and prostate, observed in humans. I am breeding MMTV Wnt1 transgenic mice to mice harboring p53 hotspot point mutations (R172H or R172P) in order to develop a model of p53 tumor suppressive action in breast cancer progression and drug response. The point mutants of p53 confer different phenotypes than a null allele, including increased metastases in the R172H mutant, and partial tumor suppression in the R172P mutant via the ability to direct cell cycle arrest and maintain genomic stability despite being unable to initiate apoptosis. How these activities will affect tumor latency, metastatic potential and chemosensitivity in the epithelial cells of the breast is of great interest.

Jeesun Kim, Ph.D.

Odyssey Fellow (2007 - 2009)
Carcinogenesis

The Role of ROS in ATM-Mediated Neurodegeneration
The central hypothesis to be tested is that ATM may promote NSCs self-renewal and differentiation in the brain through modulating intracellular redox status. Loss of ATM results in increased oxidative stress and subsequent NSCs dysfunctions through ERK-p16INK4a pathway. As a result NSCs are unable to maintain normal self-renewal and/or differentiation. My study will determine whether and how oxidative stress contributes to neurodegeneration in Atm-/- mice through the functional analysis of NSCs under oxidative stress in vivo and in vitro. To test these hypotheses, experiments described here will focus on 1) investigating the effect of ATM deficiency on NSC self-renewal and neurogenesis, 2) determining whether elevated oxidative stress affects NSC survival in Atm-/- mice and 3) identifying mechanisms how oxidative stress contributes to neuronal loss in Atm-/- mice as a regulator of NSC function.

Bhanu Pappu, Ph.D.

Odyssey Fellow (2007 - 2009)
Immunology

Characterizing the Developmental and Functional Regulation of IL-17 Producing T-Helper Cells
A novel effector CD4+ T-helper cell population that secretes interleukin-17 has been recently identified and implicated in several autoimmune and inflammatory diseases. In this study, I will first characterize the signaling and transcriptional mechanisms involved in the differentiation of Th17 cells from naïve CD4+ T cells. Second, molecular mechanisms that govern the function of Th17 effector cells will be studied. Finally, I will characterize the role of Th17 cells and IL-17 in inflammation-induced tumorigenesis. The results from this study will provide critical insights into the development and function of Th17 cells and may helpful in devising novel therapeutic interventions for inflammatory and autoimmune disease treatment.

Glauco Souza, Ph.D.

Odyssey Scholar (2007 - 2009)
Department of GU Medical Oncology

Bio-Inorganic Nanoparticles for Cancer Detection and Treatment
As we enter an age of engineering molecular assemblies, the combination of nanotechnology, synthetic biology, bioinorganic assembly and biophotonics offers remarkable opportunities for the development of tools for the diagnosis and study of diseases. Nevertheless, tailoring such nanoparticle architectures requires the challenging task of reproducibly manipulating and controlling nanoparticle assembly at the molecular level. The integration of inorganic nanoparticles and biological systems, by means of synthetic biology using bacteria to synthesize complex polymers through phage display, may offer the solution needed to overcome such challenges.Our multidisciplinary research combines nanotechnology and synthetic biology to engineer functional bioinorganic nano-assemblies. These nanostructures can reproducibly and effectively integrate various functions such as signal reporting, tissue targeting and gene/drug delivery. From the self-assembly of gold nanoparticles with phage, we construct Au-phage nanostructures (nanoshuttles) and bioinorganic hydrogels integrating unique chemical, biological, optical and mechanical properties. Such properties along with the programmable targeting capabilities of phage allow the nanoshuttles to carry both, therapeutic and detection functions, including: (i) the capability of converting near infrared (NIR) radiation into heat for targeted tissue ablation therapy, (ii) providing signal enhancement for fluorescent imaging and NIR surface enhanced Raman scattering (NIR-SERS) detection, (iii) behaving as MRI contrast agents, (iv) functioning as a 3D matrices for stem cell growth and (v) facilitating targeted gene delivery.

Lan Pham, Ph.D.

Odyssey Scholar (2006 - 2009)
Department of Hematopathology

The Role of NFAT Activation in the Pathogenesis and Biology of Non-Hogkin's Lymphoma B Cells (NHL-B)
My project is to elucidate the mechanism(s) on how an important transcription factor like nuclear factor of activated T cells (NFAT), normally expressed in activated T-lymphocytes, is constitutively expressed in aggressive lymphoma B cells. I hypothesize that NFAT is responsible for autonomous lymphoma cell growth and extended tumor cell survival through the regulation of important subset of survival genes. My aims for this study are: (1) to characterize the cellular signaling pathway(s) in NHL-B, involved in the intracellular signaling of NFAT, (2) to delineate the biologic significance of the NFAT transcription factor in the molecular and cellular biology of NHL-B and its role in dysregulating lymphomatous B cell growth and survival mechanisms in the tumor cells and (3) to develop experimental methods for molecular targeting of NFAT. I will experimentally test these aims by using lymphoma cell lines derived from lymphoma patients and primary lymphoma cells obtain from lymphoma patients. The overall goals of this project are to determine how NFAT activation not only provides the crucial signals controlling malignant cell growth and extended tumor cell survival, but also how molecular targeting and specific inhibition of NFAT expression is a promising therapeutic approach for treatment of these lymphomas.

Wenbin Ma, Ph.D.

Odyssey Fellow (2006 - 2009)
Department of Immunology

Studies of the Role of AKNA in Hematopoiesis and Tumorigenesis
Like in most cells, the maturation and function of lymphocytes (immune cells) are controlled by gene regulators called transcription factors. Our studies focus on AKNA, a transcription factor expressed by lymphoid organ and lung, which regulates the expression of genes that are important for the response of these immune cells to pathogens. To investigate the significance of AKNA, we generated two mouse models in which the gene has been inactivated by targeted mutations. In the first model we removed one part of the gene, which is needed for its binding to specific gene targets. In the second one, we have removed a much larger segment, which will completely prevent the production of the AKNA molecule. Our preliminary results suggest that the loss of AKNA results in profound defects in immune and respiratory functions. Further studies are necessary to completely assess the pathophysiological consequences of AKNA gene inactivation.

Jen-Liang Su, Ph.D.

Odyssey Scholar (2006 - 2009)
Department of Molecular & Cellular Oncology

Molecular Mechanisms for Suppression of Tumor Progression and Metastasis by E1A
In an attempt to understand the molecular mechanism of E1A-mediated chemosensitization, we found that FOXO3a is critical for E1A-mediated chemosensitization. E1A stabilize FOXO3 by preventing ubiquitin-dependent proteolysis mediated by E3 ligase ßTrCP. The binding of ßTrCP to FOXO3a requires the phosphorylation of FOXO3a at Ser644 by IKKß. E1A induces PP2A expression which is involved in inhibiting TAK1 activated IKK signaling, therefore, stabilize FOXO3a and induce chemosensitization. These results suggest that combination of E1A and paclitaxel could be an effective treatment for cancer, especially in those paclitaxel resistant patients whose basal FOXO3A expression is low.

Tomohide Yamazaki, Ph.D.

Odyssey Fellow (2006 - 2009)
Department of Immunology

Targeting Novel Costimulatory Pathways in Tumor Immunotherapy
We recently identified P6 molecule, which has Ig V-like domain in the extracellular region like B7 family molecules. We found that the fusion protein of P6 extracellular region and human IgG Fc portion binds to ConA-activated CD4+ or CD8+ T cells, which indicated us that P6 has possibility to transfer costimulatory signal to activated T cells. In order to assess the function of P6 on T cell activation and function, we activated CD4+ or CD8+ T cells with agonistic anti-CD3 antibody and P6-Ig. We found that P6-Ig inhibited CD4+ or CD8+ T cell proliferation and IL-2 production. This inhibition was maintained even in the presence of agonistic anti-CD28 antibody, which can transfer a potent stimulatory signal to CD4+ and CD8+ T cells. P6-Ig inhibited both naive and memory CD4+ T cell proliferation. Also, IL-4 and IFN production in CD4+ T cells was inhibited by P6-Ig. P6-overexpressing bone marrow-derived dendritic cells by retrovirus infection also inhibited CD4+ T cell proliferation and IL-2 production. To investigate the mechanism of P6-Ig inhibition, P6-Ig-treated CD4+ T cells were stained with propidium iodide and cell cycle was analyzed. Interestingly, P6-induced inhibition in T cell proliferation resulted in arrest of cell cycle in G0/G1 phase, but not apoptosis. To determine the distribution of P6 in immune cells and tumor cell lines, I have generated several rat anti-mouse P6 monoclonal antibodies (mAbs). This P6 mAb was highly specific for P6, when tested against B7 family molecule transfectants in FACS analysis. We are testing the capacity of anti-P6 mAbs as neutralizing agents. We hope to find the neutralizing antibody soon, and use it in functional assay in vitro and in vivo. Also, to see the function of P6 in detail, I have been engineering a P6 gene knockout construct. In summary, these results suggested that our novel costimulatory molecule, P6, is a negative regulator for T cell activation and function that arrests cell cycle of T cells during activation.

Louis Archambault, Ph.D.

Odyssey Fellow (2006 - 2009)
Department of Radiation Physics

Development of a Scintillating Fiber Dosimeter
We are developing a three dimensional detector matrix composed of plastic scintillating fibers for online assessment of radiation dose delivery in radiotherapy treatments such as intensity modulated radiation therapy (IMRT) and proton therapy. This new tool aims to improve the precision and accuracy of the quality assurance of such complex treatments. First, a matrix of 150 detectors is being currently built and tested for IMRT treatments. Furthermore, a series of Monte Carlo simulations are being conducted, in parallel, to evaluate the response of such detector system to proton radiation therapy.

Yunhe Bao, Ph.D.

Odyssey Fellow (2006 - 2008)
Department of Carcinogenesis

The Role of Chromatin Remodeling Complexes Containing Actin and Actin Related Proteins (ARPs) in DNA Damage Response
Actin and several actin-related proteins (Arps) have been identified as subunits in many chromatin modifying complexes, which play important roles in transcription and DNA repair. However, the functions of nuclear actin remain uncertain. We hypothesized that specific combinations of actin and Arps form functional modules in chromatin modifying complexes, and that these actin/Arp modules interact with specific features of chromatin to participate multiple nuclear functions. Taking advantages of the biochemically defined actin- and Arp-containing INO80 complex, and the budding yeast genetic system, we proposed to define the actin/Arp modules in chromatin modifying complexes, to determine the interactions of actin/Arp modules with chromatin and to reveal the biological functions of nuclear actin and Arps. These studies will fill the gaps in our understanding about actin and Arps in the nucleus, provide fundamental insights into the mechanisms of chromatin modifications and nuclear functions. Interestingly, during the course of the research on the INO80 complex, we noticed that some actin and Arp mutants showed DNA repair defects. These observations combined with other research ongoing in the DNA repair field have led us to a new and exciting project, which will define for the first time the role of ATP-dependent chromatin remodeling in the regulation of DNA damage sensors.

Helen Andersson, Ph.D.

Odyssey Fellow (2006 - 2008)
Department of Experimental Therapeutics

Proteasomal Targeting of Genetic Vaccines for Enhanced Antigen Degradation and Immune Presentation
Adoptive transfer of cytomegalovirus (CMV)-specific T cells expanded in vitro from donor-derived T cells can be used to prevent and treat CMV reactivation after allogeneic hematopoietic stem-cell transplantation (HSCT). However, adoptive immunotherapy after umbilical cord blood (UCB) transplantation is limited by the difficulty of generating antigen-specific T cells from functionally naïve umbilical cord blood-derived T cells. To circumvent this problem, we are using donor-derived T cells from UCB as antigen-presenting cells (T-APCs) to induce antiviral immunity in UCB transplant patients. We have previously shown that gene-modified T-APCs can successfully expand viral antigen-specific T cells ex vivo and enhance the in vivo effector function of T cells for HSCT, and we therefore believe that CMV-specific T-APCs will be a valuable tool to reduce the incidence of CMV disease after allogeneic HSCT in general and UCB transplantation in particular.

Naomi Iwai, Ph.D.

Odyssey Scholar (2006 - 2008)
Department of Molecular Genetics

Identification and Characterization of Olfactory Neural Stem Cells
Stem cells have the ability to self-renew and differentiate, and are essential for replenishment of cells in adult tissues. Since tumorigenic cells display several capacities similar to stem cells, a better understanding of stem cell behavior can have a profound impact on elucidating the cellular and molecular events leading to tumorigenesis. We chose the olfactory neural stem cells to study stem cell properties because of their continuous and robust regenerative capacity, as well as their simplicity of neuronal lineage. We are currently attempting to identify and isolate olfactory neural stem cells in the mouse. Further characterization of the stem cells will be performed by use of transgenic mouse technology.

Dae Joon Kim, Ph.D.

Odyssey Fellow (2006 - 2008)
Department of Carcinogenesis

The Role of Stat3 in UV-Induced Skin Carcinogenesis
Signal transducer and activator of transcription 3 (Stat3) is one of a family of cytoplasmic proteins that participate in normal cellular responses to cytokines and growth factors as transcription factors. Stat3 is involved in various physiological functions including apoptosis, cell cycle regulation and tumor angiogenesis and its constitutive activation is associated with a number of human epithelial cancers including skin cancer. Recent studies from our laboratory have suggested a critical role for Stat3 in UV-induced apoptosis and proliferation using transgenic mouse models. Based on previous results, the hypothesis of my project is that Stat3 activation functions to exaggerate UV-induced skin carcinogenesis by regulating keratinocyte survival following UV-induced DNA damage and subsequent keratinocyte proliferation required for development of UV-induced skin tumors. These effects of Stat3 are mediated through its regulation of critical genes involved in these cellular processes. This study will lead to a better understanding of the mechanisms controlling UV skin carcinogenesis and provide a new information on ways to prevent and treat skin cancer.

Yunfei Zhou, Ph.D.

Odyssey Fellow (2006 - 2008)
Department of Molecular Pathology

Exploration on glycolysis inhibition as a novel strategy for cancer therapy
Drug resistance is a major obstacle to successful cancer chemotherapy. Commonly seen in locally advanced solid tumors, hypoxia has been shown to decrease the efficacy of many anticancer drugs and radiotherapy. Mitochondrial respiratory dysfunction has been observed in both hematopoietic malignancies and solid tumors, and can also lead to decreased sensitivity to chemotherapeutic agents. One common metabolic feature shared by cancer cells in hypoxia and cells with mitochondrial dysfunction is that both can render the malignant cells highly glycolytic and more dependent on this pathway for ATP production. The major goals of my research project are to investigate the mechanistic link between increased glycolysis and drug resistance in cancer cells, and to test the possibility of using novel glycolytic inhibition strategy to effectively kill cancer cells with mitochondrial dysfunction and/or under hypoxic conditions. Both established cancer cell lines and stem-like cancer cell systems are used as experimental models in our studies. My current research focus is on the roles of aberrant glycolysis and its enzymes/protein complex in cell survival and apoptosis pathways. In particularly, I am interested in a possible protein complex formation involving hexokinase II, Akt and Bad protein in cancer cells. This protein complex is essential for regulation of energy metabolic homeostasis and cell survival pathways, and disruption of this complex by novel compounds that target hexokinase II will have profound impact on cancer cell survival. Furthermore, recent study suggests a link between the cell stemness and hypoxia. I am currently testing the possibility to eliminate cancer stem cells by using novel compounds to abrogate the function of hexokinase II, an enzyme essential for energy metabolism under hypoxia conditions. We anticipate that the development of effective therapeutic strategies to kill cancer cells, including stem-like cancer cells, through metabolic intervention will have important clinical implications in cancer treatment.

Zhiyong Ren, Ph.D.

Odyssey Fellow (2006 - 2008)
Department of Biochemistry & Molecular Biology

Structural Study of Peptide-Based STAT3 Inhibitors
Signal transducer and activators of transcription 3 (STAT3) is a member of the STAT protein family that relay signals from receptors of extracellular signaling protein on the cell membrane directly to the nucleus where they act as transcription activators. STAT3 plays a key role in many cellular processes such as cell growth and apoptosis, and is aberrantly activated in numerous kinds of malignant human tumors. The SH2 domain of STAT3 is indispensable for being recruited to receptors and dimer formation via reciprocal SH2 domain-phosphotyrosine interaction, which lead it to an ideal target for drug intervention. In my research, I will first use X-ray crystallography method to determine the three-dimensional structure of STAT3 protein complexed with peptidomimetic inhibitors targeting its SH2 domain. Based on the observed information of the interaction between STAT3 and the tested inhibitors, higher affinity inhibitors will be further designed and screened in a cell-free system with fluorescence polarization technique, and the leading inhibitor's activity on cell growth and apoptosis will be evaluated in breast cancer cell lines.

Catherine Allison Stewart, Ph.D.

Odyssey Fellow (2005 - 2008)
Department of Molecular Genetics

Genetic Regulation of Female Reproductive Organ Formation and Regression
Prior to sexual differentiation, mammalian embryos are sexually identical, with undifferentiated gonads, as well as Müllerian and Wolffian ducts. The Müllerian ducts give rise to female reproductive tract structures, including the oviducts, uterus, cervix and anterior vagina. Current studies are underway to determine the cellular and molecular mechanisms underlying normal development of female reproductive tract structures, with particular interest in the oviduct and uterus, in order to identify deviations that may later lead to infertility, cancer and/or disease. Treatment of ex vivo urogenital ridge cultures with inhibitors of signaling pathways in combination with microarray analysis of the perinatal oviduct and uterus have identified a number of tissue-specific genes. Future studies will investigate expression patterns of these genes, as well as their function in Müllerian duct differentiation.

Jiangong Niu, Ph.D.

Odyssey Fellow (2005 - 2008)
Surgical Oncology

The Roles of K-ras Mutations in Pancreatic Cancer
Several genetic alterations have been identified during pancreatic cancer progression, which include K-ras mutation, growth factors overexpression, and constitutive NF-kappaB activation, et al. My current research focused on the roles of these genetic alterations in pancreatic cancer progression, by establishing various in vitro cell culture models and utilizing orthotopic mouse models. These studies will provide us with a better understanding of the molecular basis of pancreatic cancer, and will help us in identifying the new therapeutic targets for this disease.

Brenton Scott, Ph.D.

Odyssey Fellow (2005 - 2008)
Department of Pulmonary Medicine

Regulation of Membrane Fusion by Sec1/Munc18 (SM) Proteins
Pneumonia is a leading cause of morbidity and mortality at MD Anderson Cancer Center. The lungs are exposed to infectious microbes with every breath, and cancer patients suffer from multiple defects in host defense. This project aims to better describe the protective and pathological roles of airway mucous secretion in the airways. This will best be accomplished by knocking out strategic genes facilitating secretion and characterizing these effects in mouse models of diseases. This information would help introduce future therapeutics to better aid cancer patients susceptible to infection and to complications from mucous hypersecretion.

Tomoya Yokota, M.D., Ph.D.

Odyssey Fellow (2005 - 2008)
Department of Experimental Radiation Oncology

Downregulation of Elafin Gene in Breast Cancer: A Novel Target
Cyclin E, a positive cell cycle regulator, is overexpressed and present in its low molecular weight (LMW) isoforms in breast cancer. The frequent appearance of the LMW forms of cyclin E is a very strong predictor of poor outcome. Elafin is an endogenous serine protease inhibitor, and plays a key role in inhibiting the synthesis of the LMW forms in normal cells. My goal is to characterize the elafin gene from the biological and biochemical aspect in breast epithelial cells. The first aim is to elucidate a precise mechanism through which the expression of elafin is specifically downregulated in breast tumor cells, and to establish C/EBPbeta-elafin pathway is involved in generation of the LMW forms. I will also provide evidence that elafin is a novel tumor suppressor gene in breast cancer.

Yongliang Zhang, Ph.D.

Odyssey Scholar (2005 - 2008)
Department of Immunology

MAP Kinase Phosphatase 5 in Antitumor Immune Responses
The detection and presentation of tumor antigens by components of innate immunity such as dendritic cells and the destruction of tumor cells by tumor specific CD8+ T cells in adaptive immunity are essential for a successful anti-tumor immune response. MAP kinases (MAPKs) are evolutionarily conserved regulators that mediate signal transduction, which play essential roles in both innate and adaptive immune. My research focuses on the negative regulation of MAPKs by MAP kinase phosphatases (MKPs) in innate and adaptive immune responses. My research goal is to boost both innate and adaptive anti-tumor immune responses by down-regulating and/or knocking out MKPs including MKP5 and MKP7 in mice. I hope that my research will lead to the finding of new therapeutic targets for anti-tumor treatments.

Hagit Dafni, Ph.D.

Odyssey Fellow (2005 - 2007)
Department of Experimental Diagnostic Imaging

MR Imaging of Tumor Vasculature and PDGFR-ß Expressing Neovasculature with Respect to Anti-Vascular Therapy
Platelet derived growth factor (PDGF) and its receptor (PDGFR), are major players in many physiological and pathological processes including regulation of interstitial fluid pressure, sprouting of blood vessels (angiogenesis) and tumor progression. The goal of this study is to develop and test a noninvasive magnetic resonance imaging (MRI)-based method for assessing PDGFR expression, activation and inhibition, specifically, in a model of prostate cancer bone metastases. Developing such a method and its later translation into the clinic will enable improved detection of early-stage PDGFR-expressing tumor and metastases, selection of the subset of tumors that will benefit from therapy targeted to PDGFR, and monitoring of targeted anti-PDGFR treatment. Results to date show that dynamic contrast enhanced MRI can be used to (a) tightly follow the changes in vascular function during tumor progression, (b) significantly indicate response (reduced vascular permeability) to short-term anti-PDGFR treatment and (c) suggest a molecular mechanism involving reduced expression of another growth factor namely VEGF. A PDGFR-targeted imaging probe is also being developed.

Maria Alejandra Loyola, Ph.D.

Odyssey Scholar (2006 - 2007)
Department of Biochemistry & Molecular Biology

Functional Connections Between the MLL Methyltransferase and Aurora Kinase B
Chromosome gain or loss often constitutes an early step in cellular transformation. Normal chromosome segregation requires coordination of many mitotic events. The Aurora family of kinases regulates some of these events. Our lab has recently discovered that the functions of the yeast homolog of Aurora kinase B are regulated by a methyltransferase Set1 that is highly related to human MLL. MLL1 is often subject to translocations associated with childhood or treatment-induced leukemias. We hypothesize that MLL and Aurora kinases share a number of substrates in vivo and aim to identify them.

Roberto Rangel, Ph.D.

Odyssey Scholar (2006 - 2007)
Department of GU Medical Oncology

Regulatory Roles for Vascular Peptidases in Angiogenesis
Angiogenesis is a complex multi-step process that can occur in development and diseases with a vascular component in response to various stimuli. Several lines of evidence indicate that angiogenesis plays a central role in both local tumor growth and distant metastasis. We hypothesize that APA and APN activities contribute to important regulatory pathways for blood vessel formation. Here, we propose to investigate the mechanisms by which APA and APN expression and activity control the physiological and pathological proliferation of activated endothelial cells forming blood vessels. The proposed experiments in this study may also lead to new mechanistic insights relevant for the development of therapies for diseases with an angiogenic component such as cancer, retinopathies, inflammation and myocardial infarction.

Fei Gao, Ph.D.

Special Fellow (2005 - 2007)
Department of Cancer Genetics

Wilms Tumor gene, Wt1, is a nuclear transcriptional factor, which was specifically expressed in metanephric mesenchyme and podocyte of glomeruli. To study the function of Wt1 gene on kidney development and normal kidney function maintenance, we generated Wt1 point mutation knock in and conditional knockout mice strains. Using these mice models, we found that Wt1 gene play a critical role during kidney development, inactivation of Wt1 results in failure of glomeruli differentiation. We also found that inactivation of Wt1 in podocyte causes mice death at 3-4 weeks old of age due to the severe renal failure, it is suggests that Wt1 is essential for normal kidney function.

Guliang Wang, Ph.D.

Special Fellow (2005 - 2007)
Department of Carcinogenesis

Chromosomal translocations resulting in inappropriate control of cancer-related genes are common features of human tumors such as leukemia and lymphoma. The causes of such genetic instabilities have yet to be clarified, but potential risk factors include environmental contaminants, radiation and genetic susceptibility. Interestingly, we noticed that the proximity of many common breakpoints on tumor-related genes to non-B-DNA structures (such as Z-DNA and H-DNA) are significantly greater than expected by chance. We hypothesize that DNA secondary structure are mutagenic "hotspots" and may contribute to human disease development. Hence, the objective of the proposed studies is to determine if the non-B DNA structures found in the breakpoint cluster regions are implicated in chromosomal breakages and to determine the endogenous and exogenous factors impacting DNA secondary structure-induced genetic stability, which may lead to the potential exploiting modulation of DNA structure for prevention and therapeutic benefit. We have now demonstrated that two types of non-B DNA structures (H-DNA and Z-DNA) are mutagenic in mammalian cells and do indeed induce DNA double-strand breaks. Our results provide a possible mechanism for the translocation breakpoints found in cancer-related genes.

Ashby Morrison, Ph.D.

Odyssey Scholar (2006 - 2007)
Odyssey Fellow (2004 - 2006)
Department of Carcinogenesis

The Role of the INO80 Chromatin-Remodeling Complex in DNA Repair
My research project investigates the Mec1/Tel1-directed involvement of the INO80 chromatin-remodeling complex in the DNA damage response. Chromatin-remodeling factors alter histones and DNA to assist nuclear processes that are regulated by the structure and form of chromatin. The yeast Mec1/Tel1 kinases, ATM/ATR in mammals, are central to the coordination of the DNA damage response and phosphorylate many proteins involved in DNA repair and cell cycle checkpoint pathways. We have found that Mec1/Tel1 kinases regulate the binding of the INO80 complex to sites of damaged DNA and also modulate the function of the complex to influence checkpoint activation during the DNA damage response. These findings establish the INO80 chromatin-remodeling complex as a functional component in the Mec1/Tel1 DNA damage signaling pathway.


© 2014 The University of Texas MD Anderson Cancer Center