In 2011, sunitinib malate (an angiogenesis inhibitor) was approved by the US FDA to treat patients with pancreatic neuroendocrine tumors. This was an important advance, however; therapeutic resistance frequently emerges over time. A better understanding of why resistance emerges and strategies to overcome resistance are needed.The goal of this project is to improve the anti-angiogeneic treatment strategy for pancreatic neuroendocrine tumor patients. Based on our preliminary data obtained from a transgenic model of PNET, we propose that distinct infiltrating innate immune cells oscillate in the tumor in response to therapy to override vascular growth restrictions and that the intratumoral monocyte composition and their expression pattern might be indicative of resistance to anti-angiogenic therapy. Utilizing a microfluidic single cell real-time PCR platform in conjunction with 8-color FACS to isolate innate immune cells from human PNET tissues and murine PNETR during therapy, we intend to understand how the distinct innate immune cell populations endorse resistance, how they oscillate to compensate for each other and how one can more successfully inhibit innate immune cell infiltration and action to re-sensitize therapy, increase response rate and prolong survival of patients undergoing antiangiogeneic therapies. Since Sunitinib has become a FDA-approved drug, we believe that the intended studies in this proposal are timely and seminal investigating mechanisms that can be translated into new treatment modalities to hopefully guide and advance the therapeutic effort in the clinic.
Rivera LB, Meyronet D, Hervieu V, Frederick MJ, Bergsland E, Bergers G. Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Cell Rep. 2015 Apr 28;11(4):577-91. doi: 10.1016/j.celrep.2015.03.055. Epub 2015 Apr 16.