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, we hypothesize that using biodegradable nanoparticles such as poly(lactic-co-glycolic acid, i.e., PLGA-NP) encapsulating therapeutic agents complexed to the binding domain of CPE, to target ovarian cancer cells, is a novel, potentially highly effective therapeutic approach to treat chemotherapy-resistant ovarian cancer. Consistent with this view, preliminary in vitro data clearly showed that fluorescein(FITC)-labeled-C-CPE effectively binds and rapidly internalizes in chemotherapy-resistant primary OSPC cell lines, suggesting that C- CPE is capable to bind and also of translocating drugs across cell tumor membrane. More importantly, preliminary in vivo results showed that CPE-PLGA-NP encapsulating a fluorescent dye (coumarin) selectively accumulate in vivo in chemotherapy resistant ovarian tumors with minimal nonspecific accumulation in RES organs and only background binding in normal cells of various other organs. Accordingly, this proposal has three related specific aims: 1) Characterize fluorescent PLGA-NP encapsulating model and therapeutic drugs, complexed to CPE peptides of different lengths (i.e., 30aa, 17aa and 9 aa), and evaluate binding activity and therapeutic efficacy of such NP in multiple in vitro assays against primary chemotherapy resistant ovarian carcinoma cell lines, 2) Examine the distribution and pharmacokinetics of PLGA-NP encapsulating coumarin complexed to 125I labeled C-CPE peptide in vivo in clinically relevant animal models of primary chemotherapy resistant ovarian carcinoma and 3) Examine the therapeutic potential of PLGA-NP encapsulating plasmid DNA encoding Diptheria Toxin A suicide protein under the control of promoter sequences of genes highly and preferentially active in ovarian cancer (i.e., mesothelin and HE4/WFDC2), complexed to CPE peptide in vivo in clinically relevant animal models of primary chemotherapy resistant ovarian carcinoma. Upon completion of this project, we will be positioned to quickly translate this research into a novel, highly effective therapeutic treatment for patients with chemotherapy-resistant disease.

Public Health Relevance

Our research group has recently discovered extremely high expression of the genes encoding the proteins claudin-3 and claudin-4 in ovarian cancer, the most lethal gynecologic malignancy. Because claudin-3 and -4 are the epithelial receptors for Clostridium perfringens enterotoxin (CPE), and are sufficient to mediate CPE binding, in the proposed research we plan to evaluate the use of biodegradable polymeric nanoparticles such as poly(lactic-co-glycolic acid, i.e., PLGA NP) encapsulating plasmid DNA encoding Diptheria Toxin A suicide protein under the control of promoter sequences of genes highly and preferentially active in ovarian cancer (i.e., mesothelin and HE4/WFDC2), complexed to the binding domain of CPE, as a novel, potentially highly effective therapeutic approach to treat chemotherapy-resistant ovarian cancer. Upon completion of this project, we will be positioned to quickly translate this research into an innovative and highly targeted therapeutic treatment for patients with chemotherapy-resistant disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA154460-03
Application #
8450911
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Fu, Yali
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$324,596
Indirect Cost
$129,546
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Menderes, Gulden; Bonazzoli, Elena; Bellone, Stefania et al. (2017) SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/Neu Expression. Clin Cancer Res 23:5836-5845
Menderes, Gulden; Bonazzoli, Elena; Bellone, Stefania et al. (2017) SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression. Gynecol Oncol 146:179-186
Cocco, Emiliano; Deng, Yang; Shapiro, Erik M et al. (2017) Dual-Targeting Nanoparticles for In Vivo Delivery of Suicide Genes to Chemotherapy-Resistant Ovarian Cancer Cells. Mol Cancer Ther 16:323-333
Menderes, Gulden; Bonazzoli, Elena; Bellone, Stefania et al. (2017) Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression. Gynecol Oncol 147:145-152
Bellone, Stefania; Bignotti, Eliana; Lonardi, Silvia et al. (2017) Polymerase ? (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro. Gynecol Oncol 144:146-152
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Zhao, Siming; Bellone, Stefania; Lopez, Salvatore et al. (2016) Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition. Proc Natl Acad Sci U S A 113:12238-12243
Cocco, Emiliano; Lopez, Salvatore; Black, Jonathan et al. (2016) Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo. Br J Cancer 115:303-11
Black, Jonathan; Menderes, Gulden; Bellone, Stefania et al. (2016) SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression. Mol Cancer Ther 15:1900-9
de Haydu, Christopher; Black, Jonathan D; Schwab, Carlton L et al. (2016) An update on the current pharmacotherapy for endometrial cancer. Expert Opin Pharmacother 17:489-99

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