Abstract 2069: Activity of an EphA2-targeted docetaxel nanoliposome in pancreatic patient-derived models as monotherapy and in combination with gemcitabine
Authors: Daryl C. Drummond, Ninfa L. Straubinger, Tista Roy Chaudhuri, Michael Moser, Walid S. Kamoun, Lia Luus, Zhaohua Richard Huang, Suresh Tipparaju, Bryan Gillard, Carl Morrison, Elizabeth Repasky, Dmitri B. Kirpotin, Robert M. Straubinger
Journal: Cancer Research (2016)

Abstract Pancreatic cancer remains one of the deadliest cancers with survival described in number of months and weeks. Recent advances in the treatment of pancreatic cancer led to the recent approval of a liposomal irinotecan (ONIVYDETM (irinotecan liposome injection), previously MM-398). Given the activity of taxanes in pancreatic cancer and the ability of nanoliposomes to deliver drugs, we developed a novel EphA2-targeted nanoliposomal docetaxel (MM-310) and evaluated its activity in patient derived xenograft (PDX) models of pancreatic cancer as a monotherapy, as well as in combination with gemcitabine. Additionally, we aimed to test the predictive potential of key biomarkers that are linked to the MM-310 mechanism of action. Several PDX models developed at Roswell Park Cancer Institute were screened for the expression of EphA2 (MM-310 target), CD31 (blood vessels), Massons Trichrome (fibrosis), CA XI (hypoxia), and E-Cadherin (adhesion molecule that can potentially inhibit target engagement). Eight EphA2+ PDX models were used to evaluate the activity of MM-310 and compare it to clinically relevant agents including nab-paclitaxel, liposomal irinotecan, oxaliplatin, and gemcitabine. We also tested the combination potential of MM-310 and gemcitabine. MM-310 was able to statistically significantly control tumor growth in all tested models with tumor regression in more than 85% of the models. When compared with standard of care agents in tumor models, at equitoxic dosing, MM-310 demonstrated greater activity to nab-paclitaxel in 80% (4/5), gemcitabine in 100% (5/5), and oxaliplatin in100% (5/5), and liposomal irinotecan in 80% (4/5). Gemcitabine is currently considered a standard of care in pancreatic cancer in combination with nab-paclitaxel, thus we conducted a study to evaluate the potential combination benefits of gemcitabine with MM-310. The combination of suboptimal doses of MM-310 and gemcitabine led to significant tumor growth control which was greater to either arm alone. Additionally, at equitoxic dosing of 50% maximum tolerated dose, MM310 + gemcitabine showed greater effect than ABRAXANE (paclitaxel protein-bound particles for injectable suspension) + gemcitabine. Although we have excluded EphA2 negative models from these studies, biomarker analysis showed that MM-310 effects are not correlated with the EphA2 expression level, suggesting that a low level EphA2 might be sufficient to mediate activity and that liposome delivery might be the rate limiting step. Additional biomarker analysis will be conducted. In conclusion, we found that MM-310 is highly active in several patient derived models of pancreatic cancer and that it was equal or greater to most standard of care agents. Future studies will aim at identifying markers for differentiating response to MM-310 (EphA2 targeted nanoliposomal docetaxel) and ONIVYDE (irinotecan liposome injection). Citation Format: Daryl C. Drummond, Ninfa L. Straubinger, Tista Roy Chaudhuri, Michael Moser, Walid S. Kamoun, Lia Luus, Zhaohua Richard Huang, Suresh Tipparaju, Bryan Gillard, Carl Morrison, Elizabeth Repasky, Dmitri B. Kirpotin, Robert M. Straubinger. Activity of an EphA2-targeted docetaxel nanoliposome in pancreatic patient-derived models as monotherapy and in combination with gemcitabine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2069.