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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.

2017 Grantee

Gorski_90x110.jpgSharon Gorski, PhD
Senior Scientist
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.

Biography
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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2016 Grantee

Xianxin Hua, MD, PhD
Professor of Cancer Biology
University of Pennsylvania Perelman School of Medicine
Philadelphia, Pennsylvania
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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2015 Grantee

Caring for Carcinoid Foundation-AACR Grant for Carcinoid Tumor and Pancreatic Neuroendocrine Tumor Research

Scott André Oakes, MD 
Associate Professor, Department of Pathology
University of California
San Francisco, California
Unfolded protein response in neuroendocrine tumors

The unfolded protein response (UPR) is an intracellular signaling pathway largely controlled by two ER transmembrane kinases—IRE1a and PERK—that communicate the protein folding status of the endoplasmic reticulum (ER) to the nucleus in order to maintain homeostasis within this organelle. Hypoxia, nutrient deprivation, proteasome dysfunction, or sustained demands on the secretory pathway, conditions often encountered by solid tumor cells, lead to the accumulation of misfolded proteins in the ER and cause "ER stress." Under remediable levels of ER stress, the UPR activates transcriptional and translational changes that promote adaptation (Homeostatic UPR). But when confronted with irremediable levels of ER stress, these adaptive measures fail, and the UPR instead switches strategies to trigger cell death (Terminal UPR).

Pancreatic neuroendocrine tumors (PanNETs) are one class of solid tumor that may be particularly sensitive to protein folding stress due to their high secretory activity. The Oakes laboratory has evidence that the UPR is upregulated and required for PanNET growth. Based on these data, they will test whether PanNETs are reliant on elevated levels of Homeostatic UPR signaling to avoid the toxic effects of protein folding stress, and if targeted interventions to either reduce Homeostatic UPR outputs or alternatively trigger the Terminal UPR will have potent antitumor effects on the growth of PanNET cells in murine xenograft models.

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2014 Grantee 

Caring for Carcinoid Foundation-AACR Grant for Carcinoid Tumor and Pancreatic Neuroendocrine Tumor Research

Herbert Chen, MD Herbert Chen, MD
Chair of the Department of Surgery
University of Alabama at Birmingham
Birmingham, Alabama
Multifunctional nanomedicine for targeted carcinoid cancer therapy

The incidence rates of carcinoid tumors increased over from 3 percent to 10 percent over the past 30 years. While surgical resection can be potentially curative, many patients develop metastatic disease precluding an operative cure. Moreover, patients with carcinoid metastases often develop malignant carcinoid syndrome with the associated endocrinopathies. This emphasizes the need for the development of new forms of therapy to prevent carcinoid cancer progression and to palliate hormone-associated symptoms.

This proposal combines the expertise of a chemical biologist who recently discovered a new and potent anticancer drug (i.e., thailandepsin A (TDP-A)), a nanotechnologist/materials chemist who develops multifunctional drug nanocarriers for targeted cancer therapy, and a surgeon/neuroendocrine cancer biologist, to develop multifunctional nanomedicines for targeted carcinoid cancer therapy. At the completion of the project, the team intends to demonstrate that TDP-A is a potent anticancer drug for carcinoid cancers and that tumor-targeting TDP-A loaded nanocarriers have the potential to significantly enhance the therapeutic efficacy in carcinoid cancers while minimizing the undesirable side effects.

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