Abstract B58: Combination therapy with the novel small molecule drug conjugate SW V-49 and gemcitabine is a potent pancreatic cancer therapeutic

Abstract

Abstract Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the ability to deliver small molecules as drug cargoes. We previously conjugated a derivative of Erastin, a small molecule with cytotoxic activity in cells bearing KRAS mutations, to sigma-2 ligand SV119, forming the novel small molecule drug conjugate SW V-49. SW V-49 demonstrated a reduction in tumor burden and improved median survival in multiple murine models of pancreatic cancer compared to either sigma-2 ligand (SV119), Erastin, or vehicle treatment alone. In the present work, we report on the selective and targeted delivery of SW V-49 to pancreatic tumors as well as the enhanced efficacy of treatment in combination with gemcitabine, a standard chemotherapeutic for pancreatic cancer. To determine delivery and uptake of SW V-49 in vivo, C57BL/6 mice bearing orthotopic KP-2 tumors were treated with SW V-49, and mass spectrometry was utilized to assess drug concentration within tissue. We observed increased delivery of SW V-49 to the tumor-bearing pancreas compared to liver, kidney, and muscle over 24 hours. To validate drug delivery in a genetically-engineered murine model, mass spectrometry was utilized to assess tissue uptake of SW V-49 in KPPC (p48-CRE/LSL-KRas/p53flox/flox) mice bearing palpable pancreatic tumors. Further evidence of SW V-49 tumor cell specificity is demonstrated by the significant reduction in EpCAM-positive neoplastic cells in the pancreatic tumors of C57BL/6 mice bearing orthotopic syngeneic KCKO tumors after treatment with SW V-49. In addition, we performed in vivo experimentation to demonstrate SW V-49 and gemcitabine combination therapy was superior in both subcutaneous and orthotopic murine models of pancreatic cancer. The KP-2 syngeneic subcutaneous tumor model demonstrated dense stroma similar to that of the human disease, and combination therapy with SW V-49 and gemcitabine resulted in significantly superior tumor reduction relative to all controls. We validated the utility of combination therapy in the KCKO syngeneic orthotopic model and again demonstrated the smallest tumor burden in the combination therapy group compared to control-treated animals. Together, these findings suggest that combination therapy utilizing the targeted therapeutic SW V-49 with systemic gemcitabine has potential translational utility. SW V-49 was successfully delivered in vivo to pancreatic tumors and reduced EpCAM-positive neoplastic cells, and combination therapy was superior to either agent alone and reduced tumor burden in multiple murine models of pancreatic cancer. Thus, SW V-49 is a promising novel therapeutic for pancreatic cancer and warrants further investigation. Citation Format: Kerri A. Ohman, Timothy M. Nywening, Suwanna Vangveravong, Dirk Spitzer, William G. Hawkins.{Authors}. Combination therapy with the novel small molecule drug conjugate SW V-49 and gemcitabine is a potent pancreatic cancer therapeutic. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B58.