Mouse Model Project Using Forward Genetics

"The development of more effective treatment regimens for patients with carcinoid metastasis and carcinoid syndrome has been hampered by the lack of effective in vivo models, which recapitulate the disease process in humans." - Dr. David Tuveson

Dr. Tuveson's laboratory will use their expertise in forward genetics and mouse cancer modeling to mutagenize enterochromaffin cells (ECCs), enteroendocrine cells found in the digestive and respiratory tracts, to both generate models of NET and simultaneously identify genes and pathways that promote NET formation.

The lack of model systems that accurately recapitulate the behavior of neuroendocrine cancers has long been a significant hurdle to developing targeted treatments for patients. This project has the promise to create faithful animal models; therefore, eliminating one of the barriers to treatment development.

Institution:

Cancer Research UK, Cambridge Research Institute

Investigator:

David Tuveson M.D., Ph.D.

Amount:

$300,000

Duration:

Two years

Research Objectives:

To establish enterochromaffic cell specific creERT2 alleles
To generate the first accurate mouse models of neuroendocrine tumors
To identify genes and pathways that cause NET formation following transposon-mediated mutagenesis in adult enterochromaffic cells

Abstract:

Patients with neuroendocrine tumors (including carcinoid) have few therapeutics options besides surgery and investigational agents, and this is a frustrating reality in my clinical practice when I encounter such patients. Currently, there is no suitable animal model that recapitulates the human diseases to allow the development of new medical interventions for NETs. Also, the cause of NET has been difficult to establish from previous studies of clinical specimens. In this application, I proposed to develop animal (mouse) models of NET by taking advantage of a new method of generating tumor models with "jumping genes" that are called transposons. Any NET that develop in such mice will then be studied to quickly determine the genes that cause NET, and this information will both be useful way to determine the cause of NET and to establish reproducible models of NET for the field. This proposal will involve the training of a new physician scientist to facilitate the development of an independent NET cancer specialist.

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