Abstract 685: Sortilin receptor-mediated novel cancer therapy: A targeted approach to inhibit vasculogenic mimicry in ovarian and breast cancers

Abstract

Abstract Rational: Vasculogenic mimicry (VM) is defined as the formation of microvascular channels by aggressive, metastatic and genetically deregulated tumor cells. This microcirculation system, independent of endothelial cells, provides oxygen and nutrients to tumor cells. Such system contributes, in part, to current chemoresistance and facilitates tumor progression as well as dissemination of cancer metastases. VM is a process associated with aggressive ovarian cancer and triple-negative breast cancer (TNBC) and is shown to correlate with decreased overall cancer patient survival. Procedures: Targeting VM in ovarian and TNBC tumors, in addition to targeting tumor cells, may thus help circumvent chemoresistance and contribute to more efficient cancer treatments. Sortilin receptor (SORT1) is essential for VM in ovarian and TNBC tumors and high expression of SORT1 in many types of cancers has been associated with their invasion and progression. Results: SORT1 was detected in 3D-tubular structures of ES-2 ovarian cancer and MDA-MB-231 TNBC cells when grown on Matrigel. Peptide-drug conjugates targeting SORT1 significantly decreased the formation of new 3D-structures by 50% (IC50) at low nM concentrations (5-10 nM). In fact, the Doxorubicin-peptide conjugate (TH1904) abolished the formation of 3D-tubular structures of ovarian cancer cells in an in vitro model, whereas unconjugated Doxorubicin or liposomal Doxorubicin (up to 20 µM) had no effect on the formation of the VM structure. Moreover, a Docetaxel-peptide conjugate (TH1902) also showed very potent in vitro activity against the formation of VM in TNBC. IC50 values for VM 3D-tubular structures inhibition was about 30 pM for TH1902 compared to 0.5 nM for Docetaxel. Conclusion: Our results provide insight into future potent ovarian and TNBC therapeutic treatments. Targeting this receptor's functions with peptide-drug conjugates may provide an efficient strategy to increase the binding/internalization of cancer drugs within tumor cells, thereby improving the efficacy of standard anticancer treatments. Our results indicate that peptide-drug conjugates targeting SORT1 strongly inhibit the formation of VM, a phenomenon associated with a more aggressive tumor phenotype and poor prognosis in patients with TNBC or ovarian cancer. Citation Format: Jean-Christophe Currie, Michel Demeule, Alain Larocque, Alain Zgheib, Richard Béliveau, Christian Marsolais, Borhane Annabi. Sortilin receptor-mediated novel cancer therapy: A targeted approach to inhibit vasculogenic mimicry in ovarian and breast cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 685.