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.
2012 GRANTEES
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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2011 GRANTEES
Xanxin Hua, M.D., Ph.D. Associate Professor, University of Pennsylvania, Philadelphia, PA
Suppression of Neuroendocrine Tumors via Epigenetic Regulation
"We have found that menin appears to suppress the signaling pathway that is regulated by a hedgehog ligand. As the Hedgehog signaling pathway is often associated with enhanced proliferation and tumorigenesis in several tissues, and menin mutations are linked to pancreatic neuroendocrine tumors, our findings raise the possibility that targeting the Hedgehog signaling pathway may be crucial for treating neuroendocrine tumors. To test this hypothesis, we will first determine the role of Gas1, a molecule that is regulated by menin and is important for optimal Hedgehog signaling, in Hh signaling and beta cell proliferation. Second, we will examine the impact of inhibiting Hh signaling on beta cell proliferation and the pancreatic neuroendocrine tumors induced by menin inhibition excision. These studies will likely unravel the crucial role of Hh signaling in the maintenance of neuroendocrine tumors, underscoring the Hh signaling pathway as an important target for therapy against neuroendocrine tumors."
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Charles M. Rudin, M.D., Ph.D.Professor, Johns Hopkins University, Baltimore, MD
Oncolytic Viral Therapy for Carcinoid and other Neuroendocrine Tumors
"My research group has focused on the development of novel cancer therapeutics, both in the laboratory and in the clinic. We have a particular interest in small cell lung cancer and other aggressive neuroendocrine cancers, including atypical carcinoid. Standard approaches to aggressive neuroendocrine cancers have changed minimally over the past 20 years. Novel therapeutic concepts are critically needed for these relatively rare but deadly cancers. My laboratory has been characterizing a novel picornavirus, SVV-001, which can selectively infect and destroy cancers with neuroendocrine differentiation. SVV-001 demonstrates a broad spectrum of activity against neuroendocrine tumors: about 50 percent of small cell carcinoma lines are permissive for the virus, as are a variety of other aggressive neuroendocrine cancers. The molecular and cellular determinants of SVV-001 permissivity have not been defined. We are seeking to identify the mechanisms of SVV-001 tumor cell entry as well as other cellular determinants of susceptibility to viral infection and lysis, using both innovative approaches and strategies that have been successfully used in defining the biology of other picornaviruses such as poliovirus. With the generous support of the Caring for Carcinoid Foundation and the American Association for Cancer Research, we will conduct a series of studies to define the basis of the selective tropism of SVV-001 for neuroendocrine tumors. These studies may identify biomarkers of viral permissivity, which will help guide subsequent clinical application of SVV-001 in patients with advanced neuroendocrine tumors. It is a terrific honor to receive this award in support of our work."
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