Ex Vivo Compound Prioritization for Gastroenteropancreatic Neuroendocrine Tumors
Researcher: Andrea Califano, PhD Location: Columbia University State: New York Year: 2015 Status: Finished
This grant was issued in partnership with Falconwood Foundation
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If successful, this study will be used to tailor therapy for neuroendocrine tumor patients on an individual basis using the drugs that are most effective in targeting their specific vulnerabilities.
This project follows the Columbia team’s identification of master regulator genes driving progression of gastroenteropancreatic neuroendocrine tumor to metastatic disease and of specific FDA approved drugs and investigational compounds that inhibit the activity of their associated proteins. These include compounds whose ability to abrogate master regulator has been validated in human tumors transplanted into immunocompromised mice. The new study aims to test the most specific and promising among these compounds to validate their ability to abrogate the aberrant activity of the identified master regulator proteins in tissue explants directly harvested from patients, which more closely represent the biology of the human tumor. This testing will be achieved using new culture technologies developed in collaborating labs, including Drs. Massimo Loda at Dana-Farber Cancer Center (DFCC) and Mary Alpaugh at Memorial Sloan Kettering Cancer Center (MSKCC). Patients will be recruited at three institutions, by collaborating oncologists, including Drs. Matthew Kulke (DFCC), Diane Reidy (MSKCC), and John Chabot (Columbia University) in the context of an exciting multi institutional collaboration
Neuroendocrine tumor (NET) metastatic progression represents the transition from a tractable to an intractable form of the disease, for which no effective treatment exists. Using a proven systems biology approach, the Califano lab at Columbia University has identified and validated master regulator genes, representing necessary drivers of the metastatic form of the disease, on an individual tumor basis. A complementary approach, based on drug perturbations in cell lines, was then used to prioritize inhibitors of master regulator activity, among FDA approved and late stage investigational compounds. This includes compounds for tumors representing five major gastroenteropancreatic neuroendocrine tumors (GEP-NET) molecular subtypes, including two pancreatic, a midgut, and two hindgut subtypes, as well as other less common subtypes. Treatment of transplanted human tumors in mice, using these drugs confirmed their prioritization, with the top candidate achieving complete response in vivo. However, before these compounds may be successfully tested in clinical studies, we will proceed to validate their ability to reverse patient-specific master regulator signatures in tissue directly harvested from patients (explants) that more closely represent the biology of the human tumor. This will be achieved using novel explant culture technologies developed by the collaborators on this proposal.
NET Research Foundation
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