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Dr. Sita Kugel of the Human Biology Division at Fred Hutchinson Cancer Research Center has received a one-year, $100,000 grant from the Neuroendocrine Tumor Research Foundation to study how a gene involved in modifying DNA may play a role in suppressing the development of pancreatic neuroendocrine tumors.
Tumors in the pancreas arise from two types of cells: exocrine cells, which make digestive enzymes, and endocrine cells, which make insulin. About 10 percent of pancreatic cancers begin as endocrine cells. Unfortunately, many patients with pancreatic neuroendocrine tumors, or PNETs, are only diagnosed after the disease has begun to spread to other sites in the body. Patients need better treatments, particularly ones that tackle metastasis.
But there are few model systems of PNETs in which scientists can gain a deeper understanding of how PNETs develop, what drives the more metastatic version of the disease, and what molecules could serve as therapeutic targets.
“This has been a real bottleneck for research,” Kugel said.
But she has developed a preclinical model system that appears to align with many of the features of human PNETs. She works on a molecule called sirtuin 6, which helps keep DNA tightly packed and genes turned off. Kugel found that loss of SIRT6 in the pancreas, in conjunction with the loss of cell cycle checkpoint gene p53, triggered spontaneous, highly metastatic tumors of the organ’s endocrine cells.
Kugel has created an even more targeted preclinical model to study how SIRT6 may work to suppress metastasis of PNETs. She will also use the grant to look more closely at SIRT6 loss in human PNETs and compare her models to clinical reality. Kugel’s work in pancreatic ductal carcinomas has suggested that tumors that are low in SIRT6 are more sensitive to certain targeted therapies. Her studies of PNETs with low SIRT6 levels may reveal if these tumors have the same susceptibility.
“We want to understand how SIRT6 is suppressing both PNETs and PNET metastasis,” Kugel said. The goal is to understand the role of SIRT6 in PNET pathogenesis.
