Treatment of Chemotherapy-Resistant Human Ovarian Cancer by Administration of CPE View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2008-2012

FUNDING AMOUNT

1366544 USD

ABSTRACT

DESCRIPTION (provided by applicant): 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. More... »

URL

http://projectreporter.nih.gov/project_info_description.cfm?aid=8068209

Related SciGraph Publications

  • 2014-01. Class III β-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel in CLINICAL & EXPERIMENTAL METASTASIS
  • 2013-12. Secretoglobin expression in ovarian carcinoma: lipophilin B gene upregulation as an independent marker of better prognosis in JOURNAL OF TRANSLATIONAL MEDICINE
  • 2013-07. Mammaglobin B (SCGB2A1) is a novel tumour antigen highly differentially expressed in all major histological types of ovarian cancer: implications for ovarian cancer immunotherapy in BRITISH JOURNAL OF CANCER
  • 2013-04. HER2 Expression Beyond Breast Cancer: Therapeutic Implications for Gynecologic Malignancies in MOLECULAR DIAGNOSIS & THERAPY
  • 2012-12. Trop-2 protein overexpression is an independent marker for predicting disease recurrence in endometrioid endometrial carcinoma in BMC CLINICAL PATHOLOGY
  • 2012-11. Claudin-6: a novel receptor for CPE-mediated cytotoxicity in ovarian cancer in ONCOGENESIS
  • 2012-10. A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer in ONCOGENE
  • 2012-04. Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy in BRITISH JOURNAL OF CANCER
  • 2011-12. Expression of Tissue factor in Adenocarcinoma and Squamous Cell Carcinoma of the Uterine Cervix: Implications for immunotherapy with hI-con1, a factor VII-IgGFcchimeric protein targeting tissue factor in BMC CANCER
  • 2011-12. Uterine and ovarian carcinosarcomas overexpressing Trop-2 are sensitive to hRS7, a humanized anti-Trop-2 antibody in JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
  • 2011-10. Tissue factor expression in ovarian cancer: implications for immunotherapy with hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor in CLINICAL & EXPERIMENTAL METASTASIS
  • 2011-10. Her2/neu extracellular domain shedding in uterine serous carcinoma: implications for immunotherapy with trastuzumab in BRITISH JOURNAL OF CANCER
  • 2010-12. Clostridium perfringens enterotoxin carboxy-terminal fragment is a novel tumor-homing peptide for human ovarian cancer in BMC CANCER
  • 2010-09. hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor for immunotherapy of uterine serous papillary carcinoma in BRITISH JOURNAL OF CANCER
  • 2010-01. In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma in BRITISH JOURNAL OF CANCER
  • 2009-12. Mammaglobin B is an independent prognostic marker in epithelial ovarian cancer and its expression is associated with reduced risk of disease recurrence in BMC CANCER
  • 2009-07. Serum amyloid A (SAA): a novel biomarker for uterine serous papillary cancer in BRITISH JOURNAL OF CANCER
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