title: A novel neutralizing antibody targeting pregnancy-associated plasma protein-a inhibits ovarian cancer growth and ascites accumulation in patient mouse tumorgrafts.
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.
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Becker
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
authors.affiliation: Division of Endocrinology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Laurie K
authors.initials: LK
authors.lastname: Bale
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
authors.affiliation: Division of Endocrinology, Mayo Clinic, Rochester, Minnesota. conover.cheryl@mayo.edu.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Conover
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001201:Ascites / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D011266:Pregnancy-Associated Plasma Protein-A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D016190:Carboplatin; D011266:Pregnancy-Associated Plasma Protein-A; D017239:Paclitaxel