Identifying Altered Epigenetic States and Drivers in Intestinal Carcinoid and Pancreatic Neuroendocrine Tumors
Researchers: Bradley Bernstein, MD, PhD; Daniel Chung, MD; Matthew Kulke, MD; Ramesh Shivdasani, MD, PhD Locations: Broad Institute, Dana-Farber Cancer Institute, Massachusetts General Hospital State: Massachusetts Year: 2013 Status: Finished
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To identify altered epigenetic states and drivers in carcinoid and pancreatic neuroendocrine tumors to identify new treatment strategies for patients. In parallel the team will also work to develop carcinoid and pancreatic neuroendocrine tumor models. These models will be used to assess potential new biomarkers and will also facilitate future research projects.
To date, few recurrent mutations have been identified in intestinal carcinoid and pancreatic neuroendocrine tumors and of the few that have been identified the majority are in genes involved in epigenetic regulation. This suggests that epigenetic changes may be underpinning the development and maintenance of carcinoid and pancreatic neuroendocrine tumors. Therefore it is necessary to understand the epigenomes of carcinoid and pancreatic neuroendocrine tumors to identify the root causes of these cancers and to identify new therapeutic targets.
With this funding, Dr. Bernstein and his collaborators will identify epigenetic alterations in carcinoid and pancreatic neuroendocrine tumors to identify new treatment strategies for patients. In the process they will build a public resource of epigenetic states, circuits and molecular dependencies for carcinoid and pancreatic neuroendocrine tumors. They will also generate new carcinoid and pancreatic neuroendocrine tumor models to assess new biomarkers and facilitate future research.
Deep characterization of genome-wide chromatin states in primary human carcinoid tumor and pancreatic neuroendocrine tumor samples, with the goal to determine the gene regulatory circuits and aberrant epigenetic states that sustain these tumors and may thus represent therapeutic opportunities.
Generation of stable new carcinoid tumor and pancreatic neuroendocrine tumor models to assess new biomarkers in carcinoid tumors and their associated stroma and to determine the significance of particular histone modifications through future perturbation studies.
Considerable effort, including exome sequencing, has identified few recurrent mutations in intestinal carcinoid and pancreatic neuroendocrine (PNETs) tumors (1) (Francis et al, Nat Genet 2013, In Press). This suggests that epigenetic changes rather than mutations may disrupt normal cell behaviors to produce and sustain these unusual, often indolent cancers. Indeed, genes that regulate chromatin, such as MEN1, ATRX and DAXX, dominate the short list of recurrent mutations in these diseases (2, 3). One effect of ATRXand DAXX mutations is to lengthen telomeres through a telomerase-independent “alternate” pathway (4, 5) but chromatin-modifying genes mutated in NETs are also implicated in transcriptional control (6, 7) and the relative importance of these distinct effects in disease pathogenesis is unclear. The epigenomes (profiles of covalent histone modifications) in primary human carcinoid tumors and PNETs might illuminate disease mechanisms and key nodes of transcriptional dysregulation, revealing both pathogenic insights and potential therapeutic targets among the root causes of these cancers.
Recent advances support this idea. First, diverse cancers carry mutations in chromatin regulator (CR) genes, including 25-75% of non-Hodgkin lymphomas, 35% of pancreas adenocarcinoma, and nearly 100% of rarer entities such as papillary thyroid and NUT midline carcinoma [reviewed in (8)]. Because such mutations are common and widespread, many drug companies have prioritized the development of epigenetic-based therapies. Thus, drugs with the potential to treat carcinoid and PNET tumors may be developed for other, more common indications; knowing the particular derangements in carcinoid and PNET tumors will help match the latter with appropriate drugs. Second, technical and computational advances now make it possible to determine epigenetic states across the genomes of normal and cancer tissues (9). In-depth characterization allows one to know exactly which chromatin modifications occur at individual genes and their regulatory elements; how these modifications respond to perturbation; which ones may be especially important for cancer pathogenesis; and which may present opportunities for therapy. Our overarching hypothesis is that epigenome (histone) alterations in carcinoid and PNET tumors will yield vulnerabilities that can be targeted with drugs. We propose to test this hypothesis in primary tumor samples, hence uncovering both inherent vulnerabilities and corresponding therapeutic opportunities (Specific Aim 1).
Fresh-frozen tumor tissue is essential for this work and we propose in parallel to use portions of the same tissue samples to achieve another vital CFCF goal: construction of new cellular models that retain the epigenetic state of the primary tumors (Specific Aim 2). We will do this as part of a wider effort between the Broad Institute and our respective cancer centers, dividing surgical specimens into portions that are suited to each goal: epigenome analysis (Aim 1) and cell model construction (Aim 2). If we are successful, the new cell models will be invaluable tools for perturbation experiments that directly test the chromatin-related hypotheses we will generate in Aim 1.
Banck MS, et al. (2013) The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest 123:2502-2508.
Jiao Y, et al. (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331:1199-1203.
Zhang J, et al. (2013) Current understanding of the molecular biology of pancreatic neuroendocrine tumors. J Natl Cancer Inst 105:1005-10017.
Lewis PW, Elsaesser SJ, Noh KM, Stadler SC, & Allis CD (2010) Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci USA 107:14075-14080.
Heaphy CM, et al. (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science 333:425.
Iwase S, et al. (2011) ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome. Nature structural & molecular biology 18:769-776.
Elsasser SJ, et al. (2012) DAXX envelops a histone H3.3-H4 dimer for H3.3-specific recognition. Nature 491:560-565.
Dawson MA & Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150:12-27.
Zhu J, et al. (2013) Genome-wide Chromatin State Transitions Associated with Developmental and Environmental Cues. Cell 152:642-654.
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