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Pancreatic Neuroendocrine Tumor Genome Project
As with other cancers, the discovery of mutated genes is essential to understand pancreatic neuroendocrine cancer. Delayed diagnosis, and the lack of good prognostic markers and new treatments can be attributed to the fact that the pathogenesis of pancreatic neuroendocrine tumors is not understood.
Dr. Papadopoulos’ team of experts proposes to sequence all 21,000 protein-coding genes in a series of pancreatic neuroendocrine tumors. Investigators will first define the genes that are mutated in a sample of twelve tumors and then determine the prevalence of the most promising mutations by sequencing the relevant genes in additional tumors.
By identifying the genetic signature of pancreatic neuroendocrine tumors, Dr. Papadopoulos’ study will lead directly to new diagnostic tools and gene-specific therapies. Additionally, the discoveries made in this study will create opportunities for advancement in the field of pancreatic neuroendocrine tumor research.
Click here to support Dr. Papadopoulos' research project.
Nickolas Papadopoulos, Ph.D.
- To identify the genetic changes underlying the development of human pancreatic neuroendocrine tumors
- To use discoveries for the development of diagnostics and new targeted therapies
Simply put, cancer is a genetic disease. Mutations in certain genes promote the growth of cancer cells. Discovery of the mutated genes is the critical step in understanding any form of cancer. Moreover, the mutations that are identified can be used to develop novel diagnostic tools and highly specific, targeted therapies. Despite their importance, little is known about the genetics of pancreatic endocrine neoplasms (pancreatic neuroendocrine tumors). The pancreatic research team at Johns Hopkins is proposing to identify the genes that are mutated in pancreatic endocrine neoplasms by sequencing all the genes that code for proteins using state-of-the-art technologies. It is our hope that this study will not only lead directly to new diagnostic tools and gene-specific therapies, but that it will also open the door to other investigators to follow-up on the discoveries we make.
In January 2011, Dr. Papadopoulos and his team uncovered the set of genetic alterations present among patients with non-functional pancreatic neuroendocrine tumors. They also uncovered a prognostic set of mutations and a rapid way of prioritizing patients for treatments with mTOR inhibiting drugs.
Dr. Papadopoulos says, "One of the most significant things we have learned is that each patient with this form of pancreatic cancer has a unique genetic code that predicts how aggressive the disease is and how sensitive it is to specific treatments."
Dr. Papadopoulos and his team found that in patients with non-functional pancreatic neuroendocrine tumors, those with specific mutations lived at least 10 years from diagnosis, while more than 60% of patients without these mutations died within five years of diagnosis. These findings, published online in Science Express, suggest new approaches for treating patients with pancreatic neuroendocrine tumors.
Alan Meeker, Ph.D., assistant professor at the Johns Hopkins Kimmel Cancer Center and a member of Dr. Papadopoulos' team, pursued these mutations and published data suggesting that both of these genes are also linked to why the ends of cellular DNA (known as "telomeres") lengthen in patients with cancer. These results were published in Science Express in June 2011.
"Finding the genes responsible for alternative lengthening of telomeres is the first step in understanding this process and provides opportunities to develop new drug therapies," says Dr. Papadopoulos.
"If the correlation holds up, we could use alternative lengthening of telomeres and ATRX/DAXX mutations as a method of determining a patient's prognosis in addition to developing treatments that target these genes," says Dr. Meeker.
With few treatment options currently available for pancreatic neuroendocrine tumor patients, these findings represent important advances toward improving treatment options for these patients.