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 anti-tumorigenic protein thrombospondin-1 (TSP-1) in bone marrow-derived cells that are recruited to metastatic sites. We report here that more than 97% of human serous ovarian tumors tested express CD36, the receptor that mediates the pro-apoptotic 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 (PDX) 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.

In search of the altering salivary proteome in metastatic breast and ovarian cancers

“…Of note, VASP and coronin-1A proteins, known to be involved in the cell migration process through ECM modulation, 39 was upregulated in CAO patients, but had lower expression in CAOAC patients, possibly in response to neoadjuvant drug therapy. 57 Metastasis promoting (by targeting the ECM substrate) proteins like MMP-9 and collagenase were upregulated in treated samples compared to untreated samples, consistent with previous studies reporting enhanced activity of these proteins, and associated with drug resistance. 56 The comparison between ovarian cancer and drugtreated ovarian cancer patients was performed to identify differentially expressed proteins that could serve as markers to monitor progression of the therapeutic influence of neoadjuvant drugs.…”

“…Similarly, prosaposin, an antimetastatic protein, inhibits the migration of ovarian cancer via stimulation of p53, was upregulated in drug-treated samples, compared to untreated samples, and could be associated with the drug sensitivity. 57 Metastasis promoting (by targeting the ECM substrate) proteins like MMP-9 and collagenase were upregulated in treated samples compared to untreated samples, consistent with previous studies reporting enhanced activity of these proteins, and associated with drug resistance. 58 Furthermore, a small proline-rich protein, previously reported to be involved in promoting ovarian cancer, 59 was significantly upregulated in drug-treated samples as compared to non-treated samples, and possibly associated with drug resistance.…”

Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF‐β1/Smad signaling pathway

“…Although several studies have reported that PSAP promotes the invasion and metastasis of prostate and breast cancer [13][14][15][16], the opposite conclusions have also been reported that PSAP can stimulate the production of TSP-1 (encoded by THBS1) in the tumor microenvironment of breast, prostate, lung and ovarian cancer [42,43]. TSP-1 can inhibit angiogenesis and induce tumor cell apoptosis via the cell surface receptor CD36 [44]. Our experiments further demonstrated that the expression of TSP-1 was unchanged after PSAP overexpression or knockdown in GBM.…”

TSP1‐CD47‐SIRPα signaling facilitates the development of endometriosis by mediating the survival of ectopic endometrium

“…These conclusions appear to contradict other studies; however, the concentration of rhTSP1 used in the current study was much lower compared with other studies. In our preliminary experiment, it was identified that the cell viability and apoptosis of NESCs were inhibited as the concentration of rhTSP1 increased 29 . Furthermore, rhTSP1 upregulates the expression of various fibrotic‐associated molecules and promotes differentiation toward fibrosis.…”