Abstract |
The majority of ovarian cancer patients acquire resistance to standard platinum chemotherapy and novel therapies to reduce tumor burden and ascites accumulation are needed. Pregnancy-associated plasma protein-A ( PAPP-A) plays a key role in promoting insulin-like growth factor (IGF) pathway activity, which directly correlates to ovarian cancer cell transformation, growth, and invasiveness. Herein, we evaluate PAPP-A expression in tumors and ascites of women with ovarian cancer, and determine the antitumor efficacy of a neutralizing monoclonal PAPP-A antibody (mAb-PA) in ovarian cancer using primary patient ovarian tumorgrafts ("Ovatars"). PAPP-A mRNA expression in patient ovarian tumors correlated with poor outcome and was validated as a prognostic surrogate in Ovatar tumors. Following confirmation of mAb-PA bioavailability and target efficacy in vivo, the antitumor efficacy of mAb-PA in multiple Ovatar tumor models was examined and the response was found to depend on PAPP-A expression. Strikingly, the addition of mAb-PA to standard platinum chemotherapy effectively sensitized platinum-resistant Ovatar tumors. PAPP-A protein in ascites was also assessed in a large cohort of patients and very high levels were evident across the entire sample set. Therefore, we evaluated targeted PAPP-A inhibition as a novel approach to managing ovarian ascites, and found that mAb-PA inhibited the development, attenuated the progression, and induced the regression of Ovatar ascites. Together, these data indicate PAPP-A as a potential palliative and adjunct therapeutic target for women with ovarian cancer.
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Authors | Marc A Becker, Paul Haluska Jr, Laurie K Bale, Claus Oxvig, Cheryl A Conover |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 14
Issue 4
Pg. 973-81
(Apr 2015)
ISSN: 1538-8514 [Electronic] United States |
PMID | 25695953
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | ©2015 American Association for Cancer Research. |
Chemical References |
- Antibodies, Monoclonal
- Antibodies, Neutralizing
- Antineoplastic Agents
- Carboplatin
- Pregnancy-Associated Plasma Protein-A
- Paclitaxel
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Topics |
- Animals
- Antibodies, Monoclonal
(administration & dosage, pharmacology)
- Antibodies, Neutralizing
(administration & dosage, pharmacology)
- Antineoplastic Agents
(administration & dosage, pharmacology)
- Ascites
(pathology)
- Carboplatin
(administration & dosage, pharmacology)
- Cell Line, Tumor
- Disease Models, Animal
- Female
- Gene Expression
- Humans
- Immunohistochemistry
- Mice
- Ovarian Neoplasms
(drug therapy, genetics, metabolism, mortality, pathology)
- Paclitaxel
(administration & dosage, pharmacology)
- Pregnancy-Associated Plasma Protein-A
(antagonists & inhibitors, genetics, metabolism)
- Prognosis
- Xenograft Model Antitumor Assays
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