Ovarian carcinoma remains the cancer with the highest mortality rate among gynecological tumors. Although many ovarian cancer patients fully respond to the standard combination of surgery and chemotherapy, nearly 90% later develop recurrent chemotherapy-resistant cancer and inevitably succumb to their disease. Thus, development of innovative, effective therapies against recurrent/chemotherapy-resistant ovarian cancer remains a high priority for improving public health. Using high-throughput technologies to analyze genetic fingerprints of ovarian cancer, we have recently discovered extremely high expression of the genes encoding the proteins claudin-3 and claudin-4. Because claudin-3 and -4 are the epithelial receptors for Clostridium perfringens enterotoxin (CPE) and are sufficient to mediate CPE binding, which triggers subsequent toxin-mediated cytolysis, we hypothesize that using CPE to target ovarian cancer cells based on their high levels of claudin-3 and -4 is potentially a novel, highly effective therapeutic approach for chemotherapy-resistant ovarian cancer. Consistent with this view, we introduced CPE to cells cultured from several primary, metastatic, and chemotherapy-resistant ovarian cancers that overexpress claudin-3 and -4, and we found that these tumor cells, unlike healthy human tissues, are highly sensitive to CPE-mediated cytolysis. More importantly, we found that intraperitoneal CPE therapy in SCID mouse xenografts harboring a highly relevant clinical model of chemotherapy-resistant human ovarian cancer inhibited tumor growth in 100% of mice harboring 1-week established disease. Thus, using CPE to target the high levels of claudin-3 and -4 may represent an innovative, potentially highly effective therapeutic approach to kill metastatic and/or chemotherapy-resistant ovarian cancer cells. Accordingly, this proposal has three related specific aims: 1) Characterize profiles and regulation of expression of claudin-3 and -4 in ovarian cancer;2) Characterize sensitivity and resistance of ovarian cancer cells to CPE-mediated cytolysis;and 3) Examine in vivo the pharmacokinetics, efficacy, and toxicity of CPE therapy. Upon completion of this project, we will be positioned to quickly translate this research into a novel clinical treatment for patients with chemotherapy-resistant disease. Ovarian carcinoma remains the most lethal of gynecologic malignancies, with up to 90% of patients diagnosed with advanced stage ovarian cancer dying from recurrent chemotherapy-resistant tumors;therefore, development of novel therapies for this disease is a high priority for improving public health. Results of the proposed research will lay the foundation for rapid clinical translation of an innovative, potentially highly effective treatment for patients with chemotherapy-resistant ovarian cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122728-02
Application #
7656777
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Song, Min-Kyung H
Project Start
2008-08-01
Project End
2012-04-30
Budget Start
2009-06-01
Budget End
2010-04-30
Support Year
2
Fiscal Year
2009
Total Cost
$346,357
Indirect Cost
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Black, Jonathan D; English, Diana P; Roque, Dana M et al. (2014) Targeted therapy in uterine serous carcinoma: an aggressive variant of endometrial cancer. Womens Health (Lond) 10:45-57
Schwab, Carlton L; English, Diana P; Roque, Dana M et al. (2014) Taxanes: their impact on gynecologic malignancy. Anticancer Drugs 25:522-35
Roque, Dana M; Buza, Natalia; Glasgow, Michelle et al. (2014) Class III ?-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel. Clin Exp Metastasis 31:101-10
Zhao, Siming; Choi, Murim; Overton, John D et al. (2013) Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A 110:2916-21
English, Diana P; Bellone, Stefania; Cocco, Emiliano et al. (2013) Oncogenic PIK3CA gene mutations and HER2/neu gene amplifications determine the sensitivity of uterine serous carcinoma cell lines to GDC-0980, a selective inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2). Am J Obstet Gynecol 209:465.e1-9
Bellone, S; Tassi, R; Betti, M et al. (2013) Mammaglobin B (SCGB2A1) is a novel tumour antigen highly differentially expressed in all major histological types of ovarian cancer: implications for ovarian cancer immunotherapy. Br J Cancer 109:462-71
Bignotti, Eliana; Tassi, Renata A; Calza, Stefano et al. (2013) Secretoglobin expression in ovarian carcinoma: lipophilin B gene upregulation as an independent marker of better prognosis. J Transl Med 11:162
Roque, Dana M; Bellone, Stefania; English, Diana P et al. (2013) Tubulin-?-III overexpression by uterine serous carcinomas is a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to epothilones. Cancer 119:2582-92
English, Diana P; Roque, Dana M; Carrara, Luisa et al. (2013) HER2/neu gene amplification determines the sensitivity of uterine serous carcinoma cell lines to AZD8055, a novel dual mTORC1/2 inhibitor. Gynecol Oncol 131:753-8
English, Diana P; Roque, Dana M; Santin, Alessandro D (2013) HER2 expression beyond breast cancer: therapeutic implications for gynecologic malignancies. Mol Diagn Ther 17:85-99

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