Abstract 5396: Targeting multiple components of the mammalian target of rapamycin (mTOR) signaling: A novel combination therapy to improve pancreatic cancer treatment.
Authors: Rajeshkumar N.V , Yabuuchi Shinichi , Patel Chirag , Pai Shweta G. , Le Dung T. , Von Hoff Daniel D. , Dang Chi V. , Maitra Anirban , Powell Jonathan 
Published: August 2014

Background and Aim: Pancreatic ductal adenocarcinoma remains a lethal malignancy with historically limited success in treatment. This study aims to (i) develop a Highly Active Anti-Tumor Therapy (HAATT) by specifically targeting multiple components of the mammalian target of rapamycin (mTOR) signaling and (ii) attempt to tailor metabolism-targeted therapy by analyzing the global metaboloic profile of tumors.

Methods: mTOR plays a central role in regulating cell growth, proliferation and survival. Here we sought to develop a therapy intend to severely harness mTOR signaling. We formulated a multi-drug regimen comprising Metformin, Rapamycin, and PP242. We investigated the effect of individual agents or in combinations, both in vitro as well as in vivo using human pancreatic cancer cell lines and patient-derived pancreatic cancer xenografts. Mice with established tumors (both s.c and orthotopically implanted) were pre-treated with 2 cycles of gemcitabine, randomized and treated with individual agents or in combinations. Tumors were harvested at various time-points and used for PD assays and functional screens including global metabolic profiles.

Results: Our studies demonstrate that the triple combination therapy specifically inactivates mTOR targets, resulting in durable suppression of tumor cell proliferation. Although, gemcitabine therapy was initially effective, but tumors resumed growth upon cessation of gemcitabine treatment. Responses to single agents or doublets were temporary and tumors grew progressively. Conversely, addition of triple combination therapy to post-gemcitabine treatment not only resulted in rapid regression of gemcitabine refractory tumors, which lasted up to 2 months, but also remarkably delayed tumor recurrence. Notably in gemcitabine refractory orthotopic model, the triple combination therapy was effective in inhibiting tumor angiogenesis resulting in the suppression of primary tumor growth. Analysis of tumor samples revealed that combination treatment remarkably suppressed tumor cell proliferation and reversed several key metabolic alterations found in gemcitabine resistant tumors.

Conclusion: Our results demonstrate that the triple combination therapy is remarkably effective in inhibiting mTOR targets, resulting in sustained tumor growth inhibition and remarkably delaying tumor recurrence in clinically relevant models established from the tumors resected from pancreatic cancer patients. Our findings have translational relevance and lay framework towards the establishment of a highly effective therapeutic strategy to substantially improve pancreatic cancer therapy.

Acknowledgement: This study is supported by a Stand Up To Cancer Dream Team Translational Cancer Research Grant (SU2C-AACR-DT0509) and funding from Commonwealth Foundation for Cancer Research.

Citation Format: N.V Rajeshkumar, Shinichi Yabuuchi, Chirag Patel, Shweta G. Pai, Dung T. Le, Daniel D. Von Hoff, Chi V. Dang, Anirban Maitra, Jonathan Powell. Targeting multiple components of the mammalian target of rapamycin (mTOR) signaling: A novel combination therapy to improve pancreatic cancer treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5396. doi:10.1158/1538-7445.AM2013-5396