Neuroendocrine Tumor Research Foundation-AACR Grants
Formerly the Caring
for Carcinoid Foundation, the Neuroendocrine Tumor Research Foundation updated
its name in 2015 to better reflect the current medical terminology for the
disease and to include all those who are affected by neuroendocrine cancer in
their community of support.
The Neuroendocrine Tumor Research Foundation-AACR Grants represent a joint effort to promote and support innovative cancer research. This grant is available to independent junior and senior investigators to develop and study new ideas and innovative approaches that have direct application and relevance to neuroendocrine tumors. Proposed research may be in any discipline of basic, translational, clinical, or epidemiological cancer research.
Sharon Gorski, PhD
Genome Sciences Center
Vancouver, BC, Canada
Proteogenomic analysis of pancreatic neuroendocrine tumors
Scientific Statement of Research
Pancreatic neuroendocrine tumors (PNETs) are an under-studied type of neuroendocrine tumor that are rare but clinically challenging due to late detection, variable progression, and frequent metastasis. The molecular basis of PNETs is not well understood and there are no prognostic markers to aid PNET clinical management. The overall aim of this study is to provide a comprehensive molecular characterization of PNETs to better understand disease progression and to devise clinically relevant subclasses. Dr. Gorski’s team has available both discovery and validation cohorts, including metastatic PNET cases. By integrating RNA-sequencing based transcriptome profiling and an innovative new technology for proteomic profiling of tumor specimens, their study will be the first to explore the proteogenomic landscape of PNETs. In addition to identifying disease classifiers, this study will lay the groundwork for further investigations of candidate biomarkers, potential driver mutations, and therapeutic targets.
Dr. Gorski completed a PhD in biology and biomedical bciences at Washington University School of Medicine, St. Louis, Missouri, in 1999. She then conducted postdoctoral studies at the British Columbia Cancer Agency where she utilized genomics approaches to study cell death and cell survival pathways. Dr. Gorski is currently a senior scientist at the BC Cancer Agency’s Genome Sciences Centre and a professor in the Department of Molecular Biology and Biochemistry at Simon Fraser University. Her research program includes analysis of cancer-related signaling pathways with a focus on breast and pancreatic cancers.
Acknowledgement of Support
We are very grateful for the 2017 Neuroendocrine Tumor Research Foundation-AACR Grant that will enable us to generate the first proteogenomics resource for pancreatic neuroendocrine tumors. This unique resource has the potential to improve the clinical management of this disease, increase our knowledge of disease progression, and identify new therapeutic avenues for patients.
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Xianxin Hua, MD, PhD
Professor of Cancer Biology
University of Pennsylvania Perelman School of Medicine
Targeting neuroendocrine tumors by suppressing a cell-surface protease
Neuroendocrine tumors (NETs), including insulinoma, can produce excessive hormones and lead to metastatic lesions and morbidity. The prevalence and incidence of neuroendocrine tumors have increased over the past few decades. The genetic causes of PNETs are diverse and heterogeneous, and understanding of the underlying molecular mechanisms is vitally important for developing new mechanism-based target therapy. Multiple endocrine neoplasia type1 (MEN1), an inherited tumor syndrome developing various endocrine tumors including pancreatic NETs (PNETs), results from a mutation in the MEN1 gene that encodes the protein menin. Thus, the menin pathway serves a valuable model for studying the mechanism for NETs. The crystal structure of menin reveals it as a scaffold protein with a central deep pocket that binds to various partners. Moreover, death-domain-associated protein (Daxx) is also frequently mutated in PNETs. However, whether and how menin and Daxx functionally interact to regulate PNET cells is currently unclear.
Dr. Xianxin Hua’s group recently found that the menin pathway and the Daxx-related pathway crosstalk to epigenetically regulate proliferation of NET cells. This interaction at least partly suppresses a cell membrane protease that is crucial for grwoth of the NET cells. Mutations in the menin or the Daxx pathway can derepress the pro-growth cell surface protease. His group proposes to pharmacologically inhibit the cell surface protease with an FDA approved drug to suppress neuroendocrine tumors in preclinical models. The proposed studies will likely lead to a new paradigm of understanding how the neuroendocrine tumors are regulated, paving the way to develop novel means to improve treatment of human NETs.
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