The Caring for Carcinoid Foundation-AACR Grants for Carcinoid Tumor and Pancreatic Neuroendocrine Tumor Research represent a joint effort to promote and support innovative cancer research. These grants are available to independent junior and senior investigators to develop and study new ideas and approaches that have direct application and relevance to carcinoid tumors or pancreatic neuroendocrine tumors. Proposed research may be in any discipline of basic, translational, clinical or epidemiological cancer research. Applications are invited from researchers currently in the field as well as from investigators with experience in other areas of cancer research who have promising ideas or research approaches that can be applied to carcinoid tumor and pancreatic neuroendocrine tumor research.
Gabriele Bergers, Ph.D.
Professor In-residence, University of California, San Francisco, San Francisco, CA
Implication of Heterogeneous Innate Immune Cells in PNET Resistance
"Implication of innate immune cells in PNET resistance: Advanced pancreatic neuroendocrine tumors (PNET) are heterogeneous tumors for which no standard therapy exists. New therapies are desperately needed to improve the quality of life and survival of PNET patients but the relative rarity of the cancer precludes testing every therapeutic combination. Inhibitors of the VEGF-signaling pathways have recently yielded promising results and sunitinib was recently FDA approved in advanced PNET patients. We intend to investigate resistance mechanisms that cause intrinsic resistance or abolish responsiveness in PNET by the anti-angiogenic agents sunitinib and sorafenib to resensitize therapy, increase response rate and prolong survival of patients undergoing anti-angiogenic therapies. We have generated a unique model of resistance to sunitinib and sorafenib in an endogenous mouse model of pancreatic endocrine tumors that accurately mimics human PNET to study evasive resistance mechanisms in response to these antiangiogenic agents. These studies will be complemented with human tumor samples. Our grant proposal investigates a novel mechanism by which we propose that distinct intratumoral monocyte populations override vascular growth restrictions in PNET. Results forthcoming can be directly translated into the clinic to offer new treatment modalities that will hopefully improve response rate as well as sustain beneficial effects in PNET patients. I feel very honored to receive the “Caring for Carcinoid Foundation-AACR grant” in support of our work."
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Eric K. Nakakura, M.D., Ph.D.
Associate Professor, Department of Surgery, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
Overcoming Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumor
"For most patients with pancreatic neuroendocrine tumors (NETs), surgery, the only potentially curative treatment, is not possible because of extensive metastatic disease. Systemic therapy options for tumor control remain limited. Dysfunction of the mTOR pathway is a critical event in pancreatic NETs. Everolimus, a partial inhibitor of mTOR, demonstrated anti-tumor activity in a phase III study leading to its approval for the treatment of pancreatic NETs. However, therapeutic resistance frequently emerges. Our goal is to use a novel in vivo model of pancreatic NETs to identify therapeutic strategies to overcome resistance to mTOR inhibition. We propose to test the hypothesis that the novel drug INK128, a complete mTOR inhibitor can overcome resistance to everolimus in pancreatic NETs. Our approach is transformative because: 1) We have the unprecedented ability to study how to overcome resistance to everolimus in pancreatic NETs using our unique animal model and a powerful new drug; and 2) We will use the radiolabeled somatostatin analog (68)Ga-DOTATOC to perform PET-CT of treated pancreatic NETs in vivo. We hypothesize that this new imaging modality will permit us to follow the response to therapy in real-time. These studies would not be possible without the crucial and generous support from The Caring for Carcinoid Foundation and The American Association for Cancer Research. Successful completion of our proposal will change the management of patients with pancreatic NETs."
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Renata Pasqualini, Ph.D.
Professor of Medicine and Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
Octreotide-Targeted Treatment of Neuroendocrine Tumors of the Pancreas
"Human pancreatic neuroendocrine tumors (NETs), including those with multiple endocrine neoplasia type 1 (MEN1) syndrome, represent a rare yet diverse cohort of tumors originating in the endocrine pancreas with limited treatment options, and fewer curative options. The collaboration proposed attempts to combine the pre-clinical Men1 conditional knockout mouse model generated in the lab of Dr. Steven Libutti with the evolving adeno-associated virus (AAV) and bacteriophage (phage) hybrid vector gene delivery system, termed AAVP, pioneered in the Arap/Pasqualini Laboratory. The Men1 mouse model, possessing homozygous inactivation of the Men1 gene in the pancreas, recapitulates the characteristics of MEN1 syndrome found in human patients and should provide a powerful tool for studying NETs of the pancreas in the context of the complicated tumor microenvironment. AAVP combines the most advantageous components of two unrelated genetic systems to produce a ligand-directed particle for targeted drug delivery. By combining the superior transduction capabilities of eukaryotic AAV and the ligand-directed targeting capabilities of prokaryotic phage, AAVP is capable of targeted delivery and transduction of mammalian cells for transgene delivery. Rather than attempting to identify new vascular addresses of pancreatic NETs, we propose to exploit the known octreotide/SSTR2 ligand/receptor pair for the delivery of a therapeutic transgene in the AAVP gene delivery system."
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