The goals of this Pathway to Independence Career Development Proposal are to request support for training to develop expertise in experimental models of ovarian cancer while addressing a fundamental gap in knowledge that could have a significant impact on the treatment of ovarian cancer patients. K99/R00 support during this transitional phase of my career will be integral to my successful development as an independent investigator at a top-tier research institute or university. The training plan outlined herein will take advantage of the extensive resources available at The Wistar Institute and neighboring University of Pennsylvania, as well as key senior personnel with track records of scientific excellence to serve as mentors, co-mentors, and collaborators. The scientific portion of this proposal focuses on experimentally and mechanistically determining the role of nucleotide metabolism in the early events in ovarian cancer tumorigenesis and whether this pathway can be targeted alone or in combination with platinum-based therapeutics to suppress chemoresistant cancer stem cells and obtain a sustained therapeutic response. The proposed studies are based on my previous findings that the rate-limiting protein in nucleotide synthesis, ribonucleotide reductase M2 (RRM2), is downregulated during oncogene-induced senescence, and an increase in nucleotides can overcome this tumor suppressive growth arrest. Additionally, RRM2 expression is highly increased in human EOC specimens and correlates with worse overall survival. I have published that knockdown or inhibition of RRM2 can decrease EOC cell growth via induction of senescence. My preliminary data show that knockdown of RRM2 can decrease aldehyde dehydrogenase 1 (ALDH1) activity, which is a marker of putative ovarian cancer stem cells (CSCs). Therefore, in line with these data I will explore two overarching scientific aims: 1) to determine whether nucleotide metabolism is increased in the early events in EOC tumorigenesis using a disease-relevant KRAS/MYC model; and 2) elucidate whether inhibition of nucleotide metabolism is synergistic with platinum treatment through a suppression of CSCs. The completion of the scientific aims of this proposal will develop my research skills in experimental models of EOC while also developing the rationale for clinical trials to obtain a sustained therapeutic response to platinum.
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy in the US. Current treatments for EOC are ineffective as the vast majority of women will have recurrent disease. Therefore, there is an urgent need to develop new ways to treat EOC patients. In this study, I will determine whether nucleotide metabolism, which leads to synthesis of the building blocks of DNA, plays a role in the early events in cancer. I will also evaluate inhibition of nucleotide metabolism in combination with current standard-of-care treatment. The results will have a direct impact on the development of novel therapeutic strategies to obtain a sustained therapeutic response.
| Singha, Bipradeb; Harper, Sandra L; Goldman, Aaron R et al. (2018) CLIC1 and CLIC4 complement CA125 as a diagnostic biomarker panel for all subtypes of epithelial ovarian cancer. Sci Rep 8:14725 |
| Bitler, Benjamin G; Wu, Shuai; Park, Pyoung Hwa et al. (2017) ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol 19:962-973 |
| Fatkhutdinov, Nail; Sproesser, Katrin; Krepler, Clemens et al. (2016) Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma. Mol Cancer Res 14:767-75 |
| Aird, Katherine M; Iwasaki, Osamu; Kossenkov, Andrew V et al. (2016) HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. J Cell Biol 215:325-334 |
| Zhu, Hengrui; Ren, Shancheng; Bitler, Benjamin G et al. (2015) SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase. Cell Rep 13:1183-1193 |
| Aird, Katherine M; Worth, Andrew J; Snyder, Nathaniel W et al. (2015) ATM couples replication stress and metabolic reprogramming during cellular senescence. Cell Rep 11:893-901 |
