We aim to elucidate the pathways and mechanisms that lead to NE malignancy and to uncover therapeutic vulnerabilities that may be exploited for treatment. We will therefore generate a ‘living biobank’ of intestinal carcinoid and pancreatic neuroendocrine tumor (NET) organoids. In conjunction with our biobank efforts, we aim to model carcinoid and pancreatic NETs through genetic engineering of relevant normal organoids. The organoids will be used for genetic, epigenetic, and drug sensitivity analysis.
Neuroendocrine tumors (NETs) are a genetically diverse set of rare tumors, which have limited treatment options. This is in part due to a currently limited understanding of the molecular pathogenesis of this disease. Furthermore, the functional role and significance of the genetic alterations that have been identified in NETs is unclear. Here we propose a two-pronged approach to address these problems. In Aim 1, we propose to build a ‘living biobank’ of NET organoids on which we will perform a comprehensive phenotypic and molecular characterization. In addition, we will generate a drug sensitivity profile for each organoid using a large panel of cancer drugs. In Aim 2, we propose to use Cas9-mediated genetic engineering to model carcinoid and pancreatic NET tumorigenesis in intestinal and pancreatic normal organoids. We will therefore induce inactivating mutations in a set of NET-associated genes and characterize the molecular and phenotypic consequences of these mutations or sets of mutations. Each of these aims is expected to elucidate mechanisms of NET formation and progression and reveal therapeutic vulnerabilities.
NET Research Foundation
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