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: David Pépin, Amanda Sosulski, Lihua Zhang, Dan Wang, Vinod Vathipadiekal, Katherine Hendren, Caroline M Coletti, Aaron Yu, Cesar M Castro, Michael J Birrer, Guangping Gao, Patricia K Donahoe
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 32 Pg. E4418-27 (Aug 11 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26216943 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Receptors, Peptide
• Receptors, Transforming Growth Factor beta
• Recombinant Fusion Proteins
• anti-Mullerian hormone receptor
• Anti-Mullerian Hormone

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Anti-Mullerian Hormone (genetics, therapeutic use)
• Ascites (metabolism)
• Biomarkers, Tumor (metabolism)
• Carcinogenesis (pathology)
• Cell Line, Tumor
• Cell Proliferation
• Dependovirus (metabolism)
• Female
• Genetic Therapy
• Humans
• Mice
• Middle Aged
• Muscles (metabolism)
• Ovarian Neoplasms (genetics, pathology, therapy)
• Receptors, Peptide (metabolism)
• Receptors, Transforming Growth Factor beta (metabolism)
• Recombinant Fusion Proteins (metabolism)
• Signal Transduction (genetics)
• Spheroids, Cellular (metabolism, pathology)
• Tissue Array Analysis
• Transgenes
• Tropism
• Tumor Burden
• Xenograft Model Antitumor Assays