Ovarian cancer continues to have the highest case-fatality ratio of any gynecologic cancer. One of the foremost barriers in the field of ovarian cancer therapeutic research is the failures of currently-established therapies to increase initial cure rates;particularly in cases of drug resistant tumors. Tumor hypoxia has been known to negatively affect chemotherapy outcomes for decades, as it can inhibit tumor cell proliferation and induce cell cycle arrest - ultimately conferring chemoresistance as anticancer drugs preferentially target rapidly-proliferating tumor cells. Attempts at overcoming hypoxia-mediated drug resistance by combining various chemotherapeutic agents has not been successful, and results in increasing the harmful effects already toxic therapies. This leads to debilitating side effects, including hematologic, neuropathic, renal and gastrointestinal toxicity which significantly diminish the quality of life of patients. STAT3 over-expression has been associated with both hypoxia and chemotherapeutic resistance in multiple tumor types. The overarching goal of this proposal is to further elucidate mechanisms of STAT3 activation in ovarian cancer, and determine how this contributes to the development of drug resistance. Additionally, we have developed a novel class of dual-function compounds based on a diarylidenyl piperidone (DAP) backbone conjugated to an N- hydroxypyrroline (NOH;a nitroxide precursor) group that have potent antineoplastic activity against ovarian cancer cells while imparting antioxidant protection to noncancerous tissues. The activity of DAP compounds is mediated by inhibition of STAT3 signal transduction. Given this DAP compounds may overcome both the problem of hypoxia related drug resistance and increased toxicity. This will be evaluated using an in vivo orthotopic ovarian cancer model. This study will advance the understanding of the fundamental mechanisms of ovarian tumorigenesis, and apply this knowledge to improve the treatment of ovarian cancer patients who develop hypoxia-mediated chemotherapy resistance. This could pave the way for clinical investigation of DAP compounds as adjuncts to current therapeutic regimens for ovarian cancer.

Public Health Relevance

While significant improvements have been made in the treatment of ovarian cancer over the past 30 years, the overall survival rates have shown only modest improvements. Most patients will eventually succumb to this devastating disease as recurrent cancers become increasingly resistant to chemotherapy, limiting treatment options. We aim to investigate a new antioxidant-promoting anticancer compound, which has been shown to be a safe and effective treatment against resistant ovarian cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Arya, Suresh
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Ohio State University
Obstetrics & Gynecology
Schools of Medicine
United States
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Dorayappan, Kalpana Deepa Priya; Wanner, Ross; Wallbillich, John J et al. (2018) Hypoxia-induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: a novel mechanism linking STAT3/Rab proteins. Oncogene 37:3806-3821
Hisey, Colin L; Dorayappan, Kalpana Deepa Priya; Cohn, David E et al. (2018) Microfluidic affinity separation chip for selective capture and release of label-free ovarian cancer exosomes. Lab Chip 18:3144-3153
Saini, Uksha; Suarez, Adrian A; Naidu, Shan et al. (2018) STAT3/PIAS3 Levels Serve as ""Early Signature"" Genes in the Development of High-Grade Serous Carcinoma from the Fallopian Tube. Cancer Res 78:1739-1750
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ElNaggar, Adam C; Saini, Uksha; Naidu, Shan et al. (2016) Anticancer potential of diarylidenyl piperidone derivatives, HO-4200 and H-4318, in cisplatin resistant primary ovarian cancer. Cancer Biol Ther 17:1107-1115
Dorayappan, Kalpana Deepa Priya; Wallbillich, John J; Cohn, David E et al. (2016) The biological significance and clinical applications of exosomes in ovarian cancer. Gynecol Oncol 142:199-205
Rath, Kellie S; Naidu, Shan K; Lata, Pushpa et al. (2014) HO-3867, a safe STAT3 inhibitor, is selectively cytotoxic to ovarian cancer. Cancer Res 74:2316-27
McCann, Georgia A; Naidu, Shan; Rath, Kellie S et al. (2014) Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor. Oncoscience 1:216-28