Dysfunction of the mTOR pathway is a critical event in pancreatic neuroendocrine tumors. A partial inhibitor of mTOR, demonstrated anti-tumor activity in a phase III study leading to its approval for the treatment of pancreatic neuroendocrine tumors. However, therapeutic resistance frequently emerges. Nakakura and colleagues will use a novel in vivo model of pancreatic neuroendocrine tumors to identify therapeutic strategies to overcome resistance to mTOR inhibition. Researchers will test the hypothesis that the novel drug INK128, a complete mTOR inhibitor can overcome resistance to everolimus in pancreatic neuroendocrine tumors. The approach is transformative because of 1) the unprecedented ability to study how to overcome resistance to everolimus in pancreatic neuroendocrine tumors using our unique animal model and a powerful new drug, and 2) the use of the radiolabeled somatostatin analog (68)Ga-DOTATOC to perform PET-CT of treated pancreatic neuroendocrine tumors in vivo. Researchers expect this new imaging modality will allow them to follow the response to therapy in real-time.
Chamberlain CE, German MS, Yang K, Wang J, VanBrocklin H, Regan M, Shokat KM, Ducker GS, Kim GE, Hann B, Donner DB, Warren RS, Venook AP, Bergsland EK, Lee D, Wang Y, Nakakura EK. A patient-derived xenograft model of pancreatic neuroendocrine tumors identifies sapanisertib as a possible new treatment for everolimus-resistant tumors. Mol Cancer Ther. 2018 Dec;17(12):2702-2709. doi: 10.1158/1535-7163.MCT-17-1204. Epub 2018 Sep 25.