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Notch1 as a Tumor Suppressor in Neuroendocrine Cancers

Funding:

American College of Surgeons - Resident Research Scholarship

Principal Investigator:

Barb Zarebczan, MD

Lab Website:

Dr. Chen's Lab

Project Summary:

Neuroendocrine (NE) tumors such as carcinoid, islet cell tumors, and medullary thyroid cancer are highly metastatic and produce numerous hormones.  These tumors are second only to colorectal carcinoma as the most common cause of isolated hepatic metastases.   While surgical resection can be curative, the majority of patients are not candidates for hepatectomy due to the degree of involvement by the NE tumors.  Therefore besides surgery, there are limited curative and palliative treatments available to patients with metastatic NE tumors, emphasizing the need for development of other forms of therapy.  These tumors also often cause debilitating symptoms, such as diarrhea, flushing, palpitations, and heart failure due to excessive hormonal secretion.  Thus, patients with incurable disease often have a poor quality of life.

Recently, we have shown that the Notch1 pathway plays an important role in controlling growth and hormone production by NE tumors.  Specifically, we have demonstrated that induction of Notch1 in human carcinoid and medullary thyroid cancer cells markedly suppresses tumor cell growth and NE hormone production. In this proposal, we will determine if pharmacologic activation of Notch1 could be a novel treatment for patients with NE tumors.

Specific aim #1: To determine the mechanism of Notch1 mRNA induction by histone deacetylase (HDAC) inhibitors.

Specific Aim #2: To determine the in vivo efficacy of pharmacologic methods of Notch1 activation in a murine model of NE tumors.

Specific Aim #3: To delineate the role of the HDAC inhibitor valproic acid (VPA) for treating patients with unresectable NE cancers: a preliminary clinical trial.

 

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First published: 07/15/02 Last updated: 11/24/09 webmaster@surgery.wisc.edu
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