? DESCRIPTION (provided by applicant): Ovarian cancer is the most deadly of gynecologic cancers because it is most often detected at late stage and little is known of its etiology. A current theory is that high grade serous, the most common ovarian cancer, originates in the fallopian tube. We propose to study pharmaceutical and chemoprevention activity of our non-toxic oral chemoprevention agent, NSC 721689 (SHetA2) in fallopian tube tissue and cells. Our drug interferes with the function of a molecular chaperone called mortalin leading to mitochondrial swelling and mitophagy that transitions to apoptosis in cancer cells, while normal cells are resistant to these effects. A clue to understanding the reason for this differential effet is an altered form of mortalin that appears in NSC-721689-treated normal epithelial cell cultures and is gradually lost as the cultures undergo stasis, immortalization and transformation. We observed mortalin overexpression in the ovarian cancer tumor microenvironment. NSC 721689 also causes G1 cell cycle arrest through phosphorylation, ubiquitination and degradation of cyclin D1; events that occur in both cancer and non- cancer cells in vitro, and in a murine chemoprevention model in vivo. Extensive preclinical studies of our drug conducted by the NCI demonstrated chemoprevention activity in vitro and in vivo, lack of mutagenic metabolites, mutagenicity or teratogenicity, no toxicity and a pharmacologic profile suitable for an oral chemoprevention agent. Our objectives are to study NSC 721689 in ovarian cancer chemoprevention producing data needed to: 1) bring this promising drug to clinical trials for ovarian cancer chemoprevention and 2) develop additional chemoprevention strategies that may be applicable to all cancers. Aim 1 will conduct a Phase 0 clinical trial to determine the number of oral NSC 721689 capsules needed to achieve micromolar drug levels in the blood of healthy volunteers and in fallopian tube tissues of patients scheduled for hysterectomy. Aim 2 will generate Dicer-Pten Double Knock Out [Dicerflox/flox Ptenflox/flox Amhr2cre/+] mice, which have been shown to develop fallopian tube tumors that spread to the ovary, and study the effects of oral NSC 721689 on fallopian tube tumor histology and multiplicity. Aim 3 will measure NSC 721689 effects on cell cycle regulatory proteins and mortalin in specimens from the clinical trial and animal model. Significant results will be validated in cultures of human fallopian tube secretory epithelial cells (hFTSECs) established from the clinical specimens. Aim 3 will also determine the identity of the NSC 721689-induced alteration in mortalin and will study how sensitivity to NSC 721689-induced autophagy and apoptosis is gained, while NSC 721689-induced mortalin alteration is lost, as hFTSECs are passaged, immortalized and transformed. Tissue microarrays (TMAs) and image analysis to separately evaluate cancer and stromal cells, reverse phase protein arrays (RPPAs) and hFTSEC/fibroblast co-cultures will be used to study the roles of mortalin and other NSC 721689 altered proteins in drug sensitivity.

R01CA196200

2015-07-01

2021-06-30