Implication of Heterogeneous Innate Immune Cells in Pancreatic Neuroendocrine Tumor Resistance
Researcher: Gabriele Bergers, PhD Location: University of California - San Francisco State: California Year: 2013 Status: Finished
This grant was issued in partnership with American Association for Cancer Research
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To develop a next generation anti-angiogenic treatment strategy for neuroendocrine tumor patients by studying resistance mechanisms.
All cells require an adequate blood supply to survive. Cancer cells, since they tend to replicate faster than normal cells, require an even greater blood supply. In order to achieve this, many tumors, including pancreatic neuroendocrine tumors, undergo angiogenesis, the development of new blood vessels.
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.
Identify and investigate the composition and function of innate immune cells in human pancreatic neuroendocrine tumors.
Elucidate the functional significance of Gr1- and Gr1+ innate immune cell oscillation in the proangiogenic relapse and identify combinatorial treatment modalities that sustain response to sunitinib and sorafenib.
Advanced pancreatic neuroendocrine tumors (PNETs) are a lethal group of tumors for which no standard therapy exists. New therapies are desperately needed to improve the quality of life and survival of PNET patients. Inhibitors of the VEGF-signaling pathways have yielded promising results and the angiogenesis inhibitor sunitinib was recently FDA approved in PNET patients with advanced disease. Notwithstanding, the beneficial effects are transient and demonstrate the limitations of one of the so far most promising drugs for PNET patients that facilitate tumor stasis instead of shrinkage and is successful only in a subset of patients. Inevitably, the tumors begin to grow again and the disease progresses, after a fleeting period of clinical benefit that is typically measured in months.
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.
NET Research Foundation
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