Abstract POSTER-THER-1432: Intraperitoneal delivery of the disintegrin vicrostatin (VCN) effectively limits ovarian cancer growth and progression

Abstract

Abstract Although prevention and early detection are the ultimate goals for ovarian cancer, the fact cannot be ignored that in 2014 21,980 women will be diagnosed with ovarian cancer in the U.S. 75% of these women will be confronted with a high stage tumor and a five-year survival rate of 45.5% (American Cancer Society, Atlanta). For these patients, improved treatment for residual disease following surgery, reduced complications during therapy as well as a decreased risk of cancer recurrence, would reduce mortality and improve their quality of life significantly. After surgery and first-line chemotherapy, 50% to 75% of responders will relapse within approximately 18 months and require further systemic therapy. Approximately 50% of women die due to carcinomatosis. Exfoliated ovarian tumor cells are carried via peritoneal fluid to secondary sites in the abdominal cavity, where they attach, invade the submesothelial connective tissue and proliferate to create peritoneal micrometastasis. These cancer cells in effusions are not amenable to surgical removal, failure of their eradication is one of the main causes for unsuccessful treatment and recurrence. The strategy of localized intraperitoneal (IP) chemotherapy targets these cells in particular and is therefore highly effective in preventing recurrence. According to the Cochrane database, IP chemotherapy successfully increased overall survival and progression free-survival, resulting in a 21.6% decrease in the risk of death. Therefore, the U.S. National Cancer Institute recommended consideration of IP chemotherapy for patients with advanced stage III ovarian cancer after optimal surgical debulking. Integrins are heterodimeric receptors that evolved to mediate complex cell-ECM interactions. These interactions regulate the ability of cells to mechanically sense their environment by integrating multiple signaling pathways initiated by extracellular cues with the cell’s cytoskeleton. Integrins (including αvβ3, αvβ5, α5β1 and αvβ6) have important roles in OC cell attachment, survival, migration, invasion and angiogenesis. However, the precise roles played by different integrin subunits in various aspects of tumor progression and why some integrins appear to be especially supportive of tumor progression are still not fully understood. Due to their pivotal roles in OC biology, integrins represent an attractive target for a novel form of OC therapy. Disintegrins are among the most potent soluble ligands of integrins representing a class of cysteine-rich polypeptides originally isolated from snake venom, many of which contain a cyclic-Arg-Gly-Asp (c-RGD) motif. These polypeptides hold a significant translational potential as anti-cancer therapeutic agents based on their high affinity interaction with integrins as well as their excellent pharmacological properties. However, these polypeptides are extremely difficult to produce recombinantly. Previously the Markland group reported that a sequence-engineered RGD-disintegrin (called vicrostatin or VCN) can be reliably produced in large quantity. Through multiple integrin ligation (i.e., αvβ3, αvβ5 and α5β1), VCN targets both endothelial and OC cells. The use of small RGD peptides or multimeric cyclic RGD peptides for targeting of integrins for both therapy and imaging of tumors has been widely reported but there is a distinct advantage to the use of disintegrins such as VCN. VCN not only acts as an antagonist (in a manner identical to RGD peptides), VCN also elicits signaling responses through direct interaction with integrins. Importantly, integrin αvβ3 is expressed at very low level on epithelial cells and mature endothelial cells, but is overexpressed on the endothelial cells of the tumor neovasculature and on tumor cells. Therefore, this integrin presents an attractive and tumor specific therapeutic target for rapidly growing solid tumors. In the present studies we delivered VCN formulated in a novel carboxymethyl cellulose (CMC) polyethyleneoxide (PEO) gel (Oxiplex™) through IP delivery. In studies described here we show that IP VCN delivery via Oxiplex™, following implantation of SKOV-3 sphereoids and confirmation of tumor growth by bioluminescent imaging, significantly reduced tumor growth and dissemination. In addition we have evaluated the dose of VCN delivered and the timing of the administrations and shown that a clinically relevant dosing schedule can be achieved. Citation Format: S. Swenson, R. Minea, J. Moore, M. Mikhail, Z. Kirakosyan & Francis S. Markland Jr. Intraperitoneal delivery of the disintegrin vicrostatin (VCN) effectively limits ovarian cancer growth and progression [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1432.