Funded Research: 2021
Dr. Haineng Xu
Research Associate In Ovarian Cancer Research Center
Department of Obstetrics & Gynecology
Perelman School of Medicine
University of Pennsylvania
Dr. Haineng Xu is a Research Associate in Ovarian Cancer Research Center, Department of Obstetrics and Gynecology at the University of Pennsylvania Perelman School of Medicine. Dr. Xu received his B.S. degree from Anhui Normal University, China, and his Ph.D. from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. During Ph.D. training, Dr. Xu focused on designing and optimizing the conditionally replicated adenovirus to specially replicated in and suppress lung and bladder cancer stem cells, overcoming drug resistance. In his prior postdoctoral training in the Department of Radiation Oncology at University of Pennsylvania, his main projects are overcoming drug resistance in glioma by targeting cancer microenvironment and glioma stem cells.
Dr. Xu’s research focus in Penn ovarian Cancer Research Center is to develop novel therapeutic strategies by exploiting the genetic vulnerabilities in ovarian cancers. He utilized the novel orthotopic patient-derived xenograft models in the preclinical trials to evaluate the drug efficacy and the mice tolerability. He explored that combination of WEE1 and ATR inhibition is effective in treating platinum- resistant ovarian and endometrial cancers and identified CCNE1 level as a biomarker for the treatment. He also discovered that the combination inhibition of PARP and ATR was able to overcome PARP resistance in ovarian cancers. Currently, Dr. Xu is discovering new treatments for ARID1A mutant clear-cell ovarian cancer (CCOC) by combination of DNA damage inhibitors with BET inhibitor. CCOC is one of the most challenging subtypes of ovarian cancers, showing poorer prognosis than other subtypes, such as the more common high-grade serous ovarian cancer. Advanced CCOC is often resistant to standard of care chemotherapy and thus has limited treatment options. To identify effective therapeutic options for this devastating disease, Dr. Xu is exploiting the most common genetic alteration ARID1A loss in CCOC, by combination inhibition of chromatin remodeling and DNA repair pathways. He will also identify new targets for combination therapies with BET inhibitor using a novel CRISPR screen in mutagenesis of functional protein domains rather than the standard CRISPR to identify functional proteins with high efficacy. The ultimate goal of Dr. Xu’s study is to identify new therapies for women with clear cell ovarian cancer in the lab and bring them to the clinic.
Dr. Heather Keys
Director of the Functional Genomics Platform
Heather Keys is the director of the Functional Genomics Platform at Whitehead Institute. She received her B.S. in Biology from the University of New Mexico and her Ph.D. in Biology from MIT. Heather is broadly interested in how the regulation of fundamental cellular processes – many of which are essential to cell survival – can impact health and disease. During her Ph.D. she used large-scale approaches to explore basic questions about the key cellular process of mRNA translation, such as how translation is affected by nutrient deprivation and how the terminal nucleotides of an mRNA impact translation initiation. As director of the Functional Genomics Platform, she develops and applies CRISPR-Cas9-based and other large-scale screening approaches to answer diverse biological questions. Much of her work in recent years has focused on using CRISPR-Cas9 screens in patient-derived ovarian cancer cells to identify modulators of therapeutic response, as well as improving delivery of the CRISPR-Cas9 machinery to enable large-scale screens in vivo.
High-grade serous ovarian cancer (HGSOC) is typically incurable, and new, effective treatment options are desperately needed. Poly(ADP-ribose) Polymerase inhibitors (PARPi) are a more recent addition to the arsenal of therapies used to treat HGSOC and improve patient survival, but patients still generally relapse and new predictive markers and combination therapies remain actively sought. Notably, PARP inhibition indirectly impacts mitochondrial metabolism. Although not previously studied in the context of PARP inhibition, altered mitochondrial metabolism of ovarian cancer cells has been associated with a cancer stem cell state, as well as therapeutic efficacy and patient outcome. Thus, understanding mitochondrial metabolism in HGSOC has great potential to impact patient care. We propose to use CRISPR-Cas9 technology to identify mitochondrial genes that can be targeted to sensitize HGSOC cells to PARPi with the goal of uncovering new targets for combination therapy. Additionally, these genes may serve as biomarkers predictive of PARPi sensitivity. In a parallel approach, we will use PARPi pre-treatment of HGSOC cells to alter their mitochondria, and then use the CRISPR-Cas9 system to uncover genes that represent PARPi-induced liabilities. Finally, we will capture the mitochondria from PARPi-treated cells and measure their metabolic composition to characterize the consequences of PARP inhibition in HGSOC. We still do not understand many of the basic principles underlying the susceptibility of ovarian cancer to particular treatments. The proposed work will contribute greatly to identification of these features and will have a broad impact on development of more precise and effective therapies.