The Peptide-Drug Conjugate TH1902: A New Sortilin Receptor-Mediated Cancer Therapeutic against Ovarian and Endometrial Cancers

SIMPLE SUMMARY: Tumor heterogeneity, drug resistance, and systemic toxicity are major concerns throughout treatments of gynecological cancers. Off-target toxicity is also a significant issue with traditional cancer medicines, preventing patients’ cancers from being adequately treated with chemotherapeutics alone. As a result, receptor-mediated targeting mechanisms are frequently exploited in conjunction with other drugs and have been the most specific among the group of techniques that have emerged in recent decades. Sortilin (SORT1) is a multifunctional protein whose expression levels have been documented in multiple malignancies, such as ovarian and endometrial tumors. In this study, the anticancer efficacy of TH1902, a peptide-docetaxel conjugate that is internalized in cancer cells through SORT1, was documented on the growth of human ovarian and endometrial cancer cell lines in vitro, as well as in mice’s tumor xenografts models, alone or in combination with carboplatin. This new anticancer drug-conjugate vectorization strategy significantly increases the efficacy of anticancer drugs towards SORT1-positive tumors, leading to a reduction in unwanted side effects. Importantly, TH1902 as a single agent or in combination with carboplatin demonstrates better efficacy than taxanes or carboplatin-taxane-based therapies for the treatment of both ovarian and endometrial cancers. ABSTRACT: Sortilin (SORT1) receptor-mediated endocytosis functions were exploited for this new approach for effective and safe treatments of gynecological cancers. Here, high expression of SORT1 was found in >75% of the clinically annotated ovarian and endometrial tumors analyzed by immunohistochemistry. Therefore, the anticancer properties of the peptide-drug conjugate TH1902, a peptide that targets SORT1 and which is linked to docetaxel molecules, were investigated both in vitro using ovarian and endometrial cancer cell cultures and in vivo using xenograft models. In vitro, TH1902 inhibited cell proliferation and triggered higher SORT1-dependent cell apoptosis than unconjugated docetaxel did in ES-2 and SKOV3 ovarian cancer cell lines. The uptake of the Alexa(488)-TH19P01 peptide from TH1902 was reduced upon siRNA-mediated silencing of SORT1. In vivo, weekly administration of TH1902 showed better tolerability compared to equivalent docetaxel doses and inhibited tumor growth in ovarian and endometrial xenograft mice models. TH1902 as a single agent inhibited ovarian tumor growth more than either of the unconjugated taxanes or carboplatin. Furthermore, TH1902 combination with carboplatin also demonstrated better efficacy when compared to both taxanes-carboplatin combinations. Overall, TH1902 shows better in vivo efficacy, compared to that of docetaxel and even paclitaxel, against SORT1-positive ovarian and endometrial cancers and could be safely combined with carboplatin.