title: Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment.
abstract: The vast majority of ovarian cancer-related deaths are caused by metastatic dissemination of tumor cells, resulting in subsequent organ failure. However, despite our increased understanding of the physiological processes involved in tumor metastasis, there are no clinically approved drugs that have made a major impact in increasing the overall survival of patients with advanced, metastatic ovarian cancer. We identified prosaposin (psap) as a potent inhibitor of tumor metastasis, which acts via stimulation of p53 and the antitumorigenic protein thrombospondin-1 (TSP-1) in bone marrow-derived cells that are recruited to metastatic sites. We report that more than 97% of human serous ovarian tumors tested express CD36, the receptor that mediates the proapoptotic activity of TSP-1. Accordingly, we sought to determine whether a peptide derived from psap would be effective in treating this form of ovarian cancer. To that end, we developed a cyclic peptide with drug-like properties derived from the active sequence in psap. The cyclic psap peptide promoted tumor regression in a patient-derived tumor xenograft model of metastatic ovarian cancer. Thus, we hypothesize that a therapeutic agent based on this psap peptide would have efficacy in treating patients with metastatic ovarian cancer.
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Suming
authors.initials: S
authors.lastname: Wang
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Harvard Medical School, Boston, MA 02115, USA. Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, University of Bergen, NO-5020 Bergen, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Blois
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College, New York, NY 10065, USA. Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: El Rayes
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Hirsch
authors.affiliation: Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, University of Bergen, NO-5020 Bergen, Norway. Department of Pathology, Haukeland University Hospital, N-5021 Bergen, Norway.
authors.forename: Karsten
authors.initials: K
authors.lastname: Gravdal
authors.affiliation: Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Palakurthi
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Diane R
authors.initials: DR
authors.lastname: Bielenberg
authors.affiliation: Centre for Cancer Biomarkers (CCBIO), Department of Clinical Medicine, University of Bergen, NO-5020 Bergen, Norway. Department of Pathology, Haukeland University Hospital, N-5021 Bergen, Norway.
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College, New York, NY 10065, USA. Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. Neuberger Berman Lung Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA. Department of Surgery, Harvard Medical School, Boston, MA 02115, USA. randy.watnick@childrens.harvard.edu.
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Watnick
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008810:Mice, Inbred C57BL; D060787:Neoplasm Grading; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000473:pathology* / Q000556:secondary; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000556:secondary; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D012044:Regression Analysis; D049231:Saposins / Q000737:chemistry*; D019700:Thrombospondin 1 / Q000494:pharmacology*; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000596:Amino Acids; D018955:CD36 Antigens; D010456:Peptides, Cyclic; D049231:Saposins; D019700:Thrombospondin 1