Matjaz Barboric, PhD
University of Helsinki
Role of mutations in transcription elongation Cdk12/CycK kinase in ovarian cancer
Better understanding of molecular mechanisms contributing to the onset of high-grade serous ovarian cancer will advance improvements in diagnosis and treatment. Dr. Barboric will investigate the deregulation of a novel transcription elongation kinase Cdk12/CycK, whose recurrent mutations have been identified recently. Using newly developed epithelial ovarian model cell lines harboring these mutations and systems biology approaches, this project will reveal how mutated Cdk12/CycK kinase perturbs gene expression programs and interactions with its associated factors, giving insight into deregulated biological processes that underlie the genesis of ovarian cancer.
Heather Cunliffe, PhD
Translational Genomics Research Institute
Defining the molecular basis of Small Cell Carcinoma of the Ovary
Small Cell Carcinoma of the Ovary (SCCO) is a lethal form of ovarian cancer striking young women and girls (average age at diagnosis is 23 years). Dr. Cunliffe hypothesizes that the very early onset and highly aggressive nature of SCCO suggests a consistent underlying genetic lesion, and thus a potential therapeutic vulnerability. The project's objective is to identify the full spectrum of molecular changes associated with SCCO to define clinically actionable targets. In addition, she proposes to develop preclinical laboratory models of SCCO to enable future studies designed to confirm mechanisms of targeted drug sensitivity, and accelerate translation of discoveries into to clinical practice.
Tyler Curiel, MD, MPH
University of Texas Health Science Center at San Antonio
Improving B7-H1 blockade to treat ovarian cancer
Immunotherapy theoretically should be effective for ovarian cancer but only has modest effects because of ovarian cancer-related immune dysfunction. Dr. Curiel will use a well-established pre-clinical mouse model to test rationally designed combinations of agents that should be synergistically useful to treat OC based on known and hypothesized mechanisms of action of selected agents and targets. Agents used are FDA-approved or already in human trials, speeding translation. The current project combines the two most effective cancer immunotherapies known based on preliminary data - anti-PD-1 and anti-B7-H1 - to test for synergy in improving immune responses against ovarian cancer.
Heidi Gray, MD
University of Washington
Behavioral and neural indices of cognitive rehabilitation in ovarian cancer
Millions of ovarian cancer survivors live with residual symptoms of impaired thinking and impaired memory severe enough to interfere with basic activities of daily living and work. However, very little is known about how to treat problems in cognition. Pharmacologic interventions have only been modestly helpful, if at all, and not all patients desire or are able to take medications. Dr. Gray will examine the ability of a 7-week cognitive rehabilitation intervention to improve memory and thinking abilities in ovarian cancer survivors. In addition, the project will measure changes in brain activity patterns from the treatment using neuroimaging.
Shelley Hooks, PhD
University of Georgia
A One-Two Punch: Dual Mechanisms for RGS inhibition of cell survival signals
Acquired chemoresistance, in which patients whose tumors initially respond to cisplatin ultimately relapse with drug-resistant disease, is a major factor in the low survival rate among ovarian cancer patients. To address this clinical problem, it is absolutely necessary to understand the molecular and genetic changes that drive the development of chemoresistance and allow ovarian cancer cells to survive in the presence of cisplatin. Dr. Hooks' lab has shown that RGS proteins are suppressed in chemoresistance and control cell sensitivity to cisplatin. The goal of the project is to test the hypothesis that RGS proteins control cell survival by two complementary pathways. The long-term benefit of this work will be to guide efforts to reverse the amplification of ovarian cancer cell survival.
Lavakumar Karyampudi, PhD
PD1 regulated dendritic cells: A target for ovarian cancer immunotherapy
Immunosuppression that prevails in ovarian tumor microenvironment is the main reason for the recurrence of disease in ovarian cancer patients. Blockade of suppressor cells and/or immune inhibitory networks during vaccination has great chance at reducing recurrence among patients. PD-1/B7-H1 axis is a major inhibitory pathway in ovarian cancer. This pathway is known to negatively regulate anti-tumor T cells but Dr. Karyampudi's recent study shows that PD-1+ dendritic cells mediate immunosuppression in ovarian cancer. This project will aim to understand these dendritic cells in order to develop successful vaccination strategies aimed at targeting PD-1/B7-H1 axis in ovarian cancer.
Ilona Kryczek, PhD
University of Michigan
Human myeloid suppressor cells maintain ovarian cancer stemness
Stem-like cancer cells are thought to play a key role in both chemoresistance and relapse, both of which can occur following treatment of advanced ovarian cancer. Stem-like cancer cells are maintained and supported by niches enriched in immune cells. Dr. Kryczek's project will document the role of myeloid-derived suppressor cells in regulating genetic and epigenetic mechanisms which stabilize and maintain stem-like cancer cells. Myeloid-derived suppressor cells massively infiltrate the ovarian cancer tumor environment (primary and metastatic tumor as well as peritoneal fluid) and utilize distinct signaling pathways, thereby contributing to the opposing biological functions that promote stability and survival of stem-like cancer cells.
Fang-Tsyr Lin, MD, PhD
Baylor College of Medicine
TRIP6 Regulates p27KIP1 to Promote Ovarian Tumorigenesis
The CDK inhibitor p27KIP1 is traditionally viewed as a tumor suppressor by inhibiting cell cycle progression. However, the cytosolic mislocalized p27KIP1 can induce ovarian cancer cell invasion. Dr. Lin has shown that these opposing effects are regulated through the interaction of p27KIP1 with the adaptor protein TRIP6, which is expressed at high levels in ovarian cancers. TRIP6 cooperates with AKT to promote the oncogenic effect of cytosolic p27KIP1 but regulates growth factor-induced nuclear p27KIP1 degradation to promote cancer cell proliferation. This project aims to elucidate the novel mechanisms and consequences of these regulations to find better strategies for ovarian cancer therapy.
Meera Nanjundan, PhD
University of South Florida
Role of Autophagy in the Transition from Endometriosis to Ovarian Cancers
Dr. Nanjundan proposes that endometriosis, an inflammatory gynecological disease, is a "precursor lesion" leading to the development of endometrioid/clear cell ovarian cancers. Although less frequent relative to serous ovarian cancers, often the prognosis is worse. This project will investigate whether "autophagy," a survival mechanism which could be activated in response to iron (a product of heme elevated in endometriotic cysts), is involved in the transition from endometriosis to ovarian cancer.
Jeremy Stark, PhD
Beckman Research Institute of the City of Hope
Homology-Directed Repair Deficiency in Ovarian Cancer
Cancer cells that are able to perform homology-directed repair (HDR) can be resistant to PARP inhibitor therapeutics, which are purposefully designed to cause DNA damage. Many ovarian cancers apparently lack the HDR pathway, and hence are likely to be sensitive to PARP inhibitor therapy. Dr. Stark has found that HDR-deficient cells show biomarkers for unstable DNA. This project will determine whether these biomarkers for unstable DNA can identify individual ovarian cancers that have lost the HDR pathway, and hence are likely to be responsive to PARP inhibitor therapy. Accurately identifying ovarian cancer patients that will likely respond to PARP inhibitor will accelerate the development of this promising therapeutic approach.