Understanding the Tumor Suppressor Activities of ATRX-Daxx through Epigenomic Profiling and Animal Models
Researcher: Peter Lewis, PhD Location: University of Wisconsin-Madison State: Wisconsin Year: 2012 Status: Finished Award: Mary Terese Hartzheim Award for Neuroendocrine Tumor Research
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To create models to understand the role of ATRX and Daxx in neuroendocrine tumor development with the ultimate goal of developing new therapies for patients by targeting these processes and to establish the precise changes in chromosome structure resulting from mutations in ATRX and Daxx.
The chromosomes in our cells are composed of equal amounts of DNA and protein. The cellular machine of ATRX-Daxx helps to build and maintain chromosome structure at specific sites in our genome, including telomeres, the special structures that cap and protect the ends of our chromosomes.
Previous CFCF-funded researchers discovered mutations in the genes ATRX and Daxx among tumors from patients with non-functioning pancreatic neuroendocrine tumors. Despite these exciting and promising findings, the precise role of ATRX and Daxx in neuroendocrine tumor development is yet to be understood and treatments exploiting these findings have yet to be developed.
Dr. Lewis began working on this project alongside Dr. C. David Allis at The Rockefeller University. We are delighted that Dr. Lewis will be establishing his own lab at the University of Wisconsin-Madison, made possible by support from the MTH Foundation.
Dr. Lewis’ team will conduct experiments and create models to understand the role of ATRX and Daxx in neuroendocrine tumor development with the ultimate goal of developing new therapies for patients by targeting these processes. Furthermore they will establish the precise changes in chromosome structure resulting from mutations in ATRX and Daxx. Knowledge of these changes could shed light on not only neuroendocrine cancers but many other cancer types as well.
(This grant was first awarded to C. David Allis, PhD, The Rockefeller University)
Transcriptome and epigenomic analyses of pancreatic neuroendocrine tumor subtypes
Faithfully recapitulate pancreatic neuroendocrine tumor initiation and progression through conditional deletion of ATRX and Daxx tumor suppressors
In this research project Dr. Lewis and his team will conduct a set of experiments to understand 1) why pancreatic neuroendocrine cells that lack ATRX-Daxx are more likely to become tumor cells and 2) how ATRX-Daxx act as tumor suppressors in pancreatic neuroendocrine cells.
Specifically they will focus on understanding how chromosome structure and the turning on and off of genes change when pancreatic neuroendocrine cells lack ATRX-Daxx. Results from these studies will identify new molecular targets for novel treatments for neuroendocrine tumor patients.
This project will: identify new molecular targets for neuroendocrine tumor treatment, diagnosis and prognosis; generate mouse models to test new, targeted therapies for patients; and determine how mutations in ATRX and Daxx affect chromosome structure in neuroendocrine tumors.
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