Abstract PO030: A novel integrin-targeted therapeutic agent for prostate cancer

Abstract

Abstract Disintegrins are disulfide-rich peptides, many containing an Arg-Gly-Asp (RGD) motif. They hold significant translational potential as anti-cancer agents based on their high-affinity/high-specificity interaction with tumor integrins and desirable pharmacological attributes. The integrin-binding activity of disintegrins depends on a mobile 11-amino acid loop displaying the RGD tripeptide motif or some other tripeptide motif. They bind only to the activated conformation of integrins on motile cancer cells and angiogenic endothelial cells. We designed a sequence-engineered RGD-disintegrin, vicrostatin (VCN), that can be produced at ~200mg/L from cell lysates of a bacterial recombinant system. VCN, a monomer (MW=7146), inhibits tumor cell adhesion and dissemination, and angiogenic endothelial cell invasion and tube formation. Integrins are cell surface adhesion receptors (containing a and b chains) operating at the interface between the extracellular matrix and cytoskeletal apparatus. A sub-group of integrins recognize the RGD sequence present in key extracellular matrix proteins involved in prostate cancer (PC) growth and dissemination. Integrins are involved in bi-directional signaling interactions that alter cellular functions. Among these interactions are those involved in PC growth, metastasis and angiogenesis. Integrin avb3 plays an important role in the development of bone metastases, supporting our belief that it, as well as other RGD-integrins, are important therapeutic targets in advanced PC. We examined the effect of treatment of a xenograft model of human PC using a liposomal formulation of VCN (LVCN). PC3 cells were implanted subcutaneously in 5-week old male nude mice. LVCN and VCN (100µg VCN equivalent per dose) administration was initiated IV when tumors became palpable (14 days). Tumor size was measured weekly by caliper in a blinded study. There was a 75% reduction in tumor growth in LVCN-treated animals compared to controls. VCN displayed little anti-tumor activity most likely due to its lack of availability to the PC cells. We also examined the anti-angiogenic activity of LVCN in this model using CD31/PECAM immunohistochemistry and observed a significant decrease in tumor-associated microvessel density. We then evaluated therapeutic efficacy of LVCN in treating bone metastases. CWR22rV1 PC cells were suspended in a solution of matrigel and injected into a drilled hole in the proximal left tibia of immunodeficient mice (100,000 cells/10µL). Following injection, the diameters of both tibias were measured by caliper twice weekly. Since CWR22rV1 cells are androgen dependent, animals received daily injections of testosterone. Tumors grew slowly initially, but at 20 days tumors were evident and treatment began. LVCN and VCN were administered twice weekly via IV injection (100µg per dose) for 5 weeks. LVCN displayed ~81% inhibition of tumor growth compared to VCN, PBS or empty liposomes. Our findings provide strong support for the effectiveness of LVCN as an inhibitor of PC growth and metastases. Citation Format: Francis S. Markland, Stephen Swenson, Radu Minea, Jacek Pinski. A novel integrin-targeted therapeutic agent for prostate cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO030.