The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that arise from the stomach, pancreas, or intestinal tract continues to rise. While GEP-NETs grow slowly, they are nonetheless incurable and lethal when advanced. Despite progress, effective systemic treatments for GEP-NETs remain limited. Data from placebo arms of human clinical trials indicate that GEP-NETs take a median of 5-18 months to increase 20% or more in diameter. This slow growth has resulted in a scarcity of clinically relevant models necessary for studying GEP-NET biology and etiology and performing drug testing and screening. Consequently, progress in identifying new treatment targets and more effective th...

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The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that arise from the stomach, pancreas, or intestinal tract continues to rise. While GEP-NETs grow slowly, they are nonetheless incurable and lethal when advanced. Despite progress, effective systemic treatments for GEP-NETs remain limited. Data from placebo arms of human clinical trials indicate that GEP-NETs take a median of 5-18 months to increase 20% or more in diameter. This slow growth has resulted in a scarcity of clinically relevant models necessary for studying GEP-NET biology and etiology and performing drug testing and screening. Consequently, progress in identifying new treatment targets and more effective therapies has been limited. To address this challenge, we will generate and evaluate innovative in vitro and in vivo laboratory models from tumors removed from patients with diverse GEP-NETs. These models will incorporate temporal doxycycline-controlled genetic modifications that will allow us to "turn on" a growth stimulus, facilitating tumor cell expansion and growth to provide sufficient materials and resources for translational studies. Importantly, these models will also allow us to subsequently "turn off" the growth switch to return them to their original tumor biological state, enabling comprehensive drug testing and screening, and the exploration of drug combinations to identify optimal treatments to destroy GEP-NETs. Preliminary studies have demonstrated that our approach could indeed generate in vitro and in vivo GEP-NET models. If funded, we will establish a biobank of intestinal NET and pancreatic NET models representing the spectrum of diversity in human NET behavior. We will further genetically and molecularly characterize these models and conduct the testing of known active drugs and screen a chemotherapy drug library on these models to identify more effective GEP-NET treatments, ultimately improving patient outcomes.

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