title: AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer.
abstract: To improve ovarian cancer patient survival, effective treatments addressing chemoresistant recurrences are particularly needed. Mullerian inhibiting substance (MIS) has been shown to inhibit the growth of a stem-like population of ovarian cancer cells. We have recently engineered peptide modifications to human MIS [albumin leader Q425R MIS (LRMIS)] that increase production and potency in vitro and in vivo. To test this novel therapeutic peptide, serous malignant ascites from highly resistant recurrent ovarian cancer patients were isolated and amplified to create low-passage primary cell lines. Purified recombinant LRMIS protein successfully inhibited the growth of cancer spheroids in vitro in a panel of primary cell lines in four of six patients tested. Adeno-associated virus (AAV) -delivered gene therapy has undergone a clinical resurgence with a good safety profile and sustained gene expression. Therefore, AAV9 was used as a single i.p. injection to deliver LRMIS to test its efficacy in inhibiting growth of palpable tumors in patient-derived ovarian cancer xenografts from ascites (PDXa). AAV9-LRMIS monotherapy resulted in elevated and sustained blood concentrations of MIS, which significantly inhibited the growth of three of five lethal chemoresistant serous adenocarcinoma PDXa models without signs of measurable or overt toxicity. Finally, we tested the frequency of MIS type II receptor expression in a tissue microarray of serous ovarian tumors by immunohistochemistry and found that 88% of patients bear tumors that express the receptor. Taken together, these preclinical data suggest that AAV9-LRMIS provides a potentially well-tolerated and effective treatment strategy poised for testing in patients with chemoresistant serous ovarian cancer.
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114;
authors.forename: David
authors.initials: D
authors.lastname: Pépin
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114;
authors.forename: Amanda
authors.initials: A
authors.lastname: Sosulski
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114;
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01655;
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Gynecological Oncology, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02114.
authors.forename: Vinod
authors.initials: V
authors.lastname: Vathipadiekal
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114;
authors.forename: Katherine
authors.initials: K
authors.lastname: Hendren
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114;
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Coletti
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114;
authors.forename: Aaron
authors.initials: A
authors.lastname: Yu
authors.affiliation: Gynecological Oncology, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02114.
authors.forename: Cesar M
authors.initials: CM
authors.lastname: Castro
authors.affiliation: Gynecological Oncology, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02114.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01655;
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114; pdonahoe@partners.org.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000235:genetics* / Q000627:therapeutic use*; D001201:Ascites / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000229:Dependovirus / Q000378:metabolism*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018000:Receptors, Peptide / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D046888:Tissue Array Analysis; D019076:Transgenes; D018523:Tropism; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone
keywords: AAV9; MIS; PDX; anti-Mullerian hormone; ovarian cancer