Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment
Menée à l'aide de xénogreffes dérivées de cellules tumorales prélevées sur une patiente atteinte d'un cancer métastatique de l'ovaire, cette étude met en évidence des mécanismes d'activité antitumorale d'un peptide cyclique conçu à partir de la séquence active de la prosaposine, une protéine naturellement dotée de propriétés antimétastatiques
Although approved drugs for ovarian cancer are available, this remains a difficult disease to overcome, and most ovarian cancer patients cannot be successfully treated, particularly in the setting of advanced disease. Wang et al. determined that prosaposin, a naturally occurring protein with antimetastatic properties, can promote regression of ovarian cancer because of its effects on thrombospondin, another antitumorigenic protein, which targets a receptor called CD36. The authors generated a cyclic peptide modeled on the active site of prosaposin and showed that the new peptide is very effective in treating mice with patient-derived xenografts of metastatic ovarian cancer, suggesting that this peptide is a candidate for future testing in human patients.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.