Ovarian cancer is the deadliest gynecological disease in the United States, which is due in part to the lack of understanding on how the cancer becomes resistant to chemotherapies. Established (cisplatin) and emerging anti-cancer therapeutics (PARPi) effectiveness rely heavily on intrinsic DNA damage response. Recent reports have observed that cisplatin-resistant cancer cells are cross-resistant to PARP inhibitors. Preliminary experiments in ovarian cancer indicate that aberrant Wnt signaling contributes to resistant to both cisplatin and PARPi by modulating the non-homologous end-joining (NHEJ) pathway. The overall goals of the proposed research is to elucidate the mechanism of Wnt-dependent PARPi/cisplatin resistant in ovarian cancer and to develop a translational approach to re-sensitize tumor cells. During the mentored K99 phase, I will work to clearly establish the impact aberrant Wnt signaling (e.g. loss off Wnt5a) and NHEJ has in conveying or maintaining chemoresistance in ovarian cancer cells. I will then determine the in vivo significance of inhibiting canonical Wnt and NHEJ pathways in the context of resistant disease. I will pursue the establishment of pre- clinical models of ovarian cancer (patient-derived xenograft) to determine if the modulation of Wnt signaling or NHEJ could be translated into the clinical setting to aid in the treatment of chemoresistant ovarian cancer. Excitingly, the proposed work will contribute to the elucidation of the resistant process and could have a direct impact on future therapeutic strategies for ovarian cancer.
Ovarian cancer is the deadliest gynecological disease in the United States. Over 75% of all ovarian cancer treated with traditional chemotherapies will recur and be resistant to anti-cancer drugs (cisplatin). There is an urgent need to better understand how ovarian cancer becomes resistant and how to clinically treat patients with resistant disease. The work detailed in this proposal would help to answer these critical questions. Specifically, I will examine traditional (cisplatin) and emerging (PARP inhibitors) ovarian cancer therapies to determine cellular properties involved in conveying and maintaining resistance. In addition, the work examines a potential novel therapeutic approach in dealing with chemoresistant ovarian cancer.
| Wu, Shuai; Fatkhutdinov, Nail; Fukumoto, Takeshi et al. (2018) SWI/SNF catalytic subunits' switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells. Nat Commun 9:4116 |
| Wheeler, Lindsay J; Watson, Zachary L; Qamar, Lubna et al. (2018) CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer. Oncogenesis 7:92 |
| Fukumoto, Takeshi; Park, Pyoung Hwa; Wu, Shuai et al. (2018) Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer. Cell Rep 22:3393-3400 |
| Fukumoto, Takeshi; Zhang, Rugang; Bitler, Benjamin G (2018) Epigenetic inhibitors for the precision treatment of ARID1A-mutant ovarian cancers: what are the next steps? Expert Rev Precis Med Drug Dev 3:233-236 |
| Bitler, Benjamin G; Watson, Zachary L; Wheeler, Lindsay J et al. (2017) PARP inhibitors: Clinical utility and possibilities of overcoming resistance. Gynecol Oncol 147:695-704 |
| Karakashev, Sergey; Zhu, Hengrui; Yokoyama, Yuhki et al. (2017) BET Bromodomain Inhibition Synergizes with PARP Inhibitor in Epithelial Ovarian Cancer. Cell Rep 21:3398-3405 |
| Baumgartner, Heidi K; Rudolph, Michael C; Ramanathan, Palaniappian et al. (2017) Developmental Expression of Claudins in the Mammary Gland. J Mammary Gland Biol Neoplasia 22:141-157 |
