Grant: Project Grant

Secondary, or metastatic, brain cancers are ten times more common than cancers that originate in the brain. These typically spread to the brain from lung cancers, breast cancers, and melanomas. The current standard of care is surgery and/or radiation therapy. Metastatic brain cancers have a 90% mortality rate within one year of diagnosis. Dr. Singh's laboratory has developed animal models of brain metastases and discovered "pre-metastatic" brain metastasis-initiating cells (BMICs). These cells are "newly arrived" in the brain and have yet to form detectable tumors. These pre-metastatic BMICs are a unique and important new cellular target for the development of a new class of future cancer therapeutics designed to prevent brain metastasis. A screening of small molecules, informed by a gene expression analysis technology, has led to the discovery that inhibition of an enzyme called inosine-5-monophosphate dehydrogenase (IMPDH) prevents the growth of BMICs. Our team now proposes to pursue the next phase of this pre-clinical drug development program focused optimizing the structures of previously-known IMPDH inhibitors to enhance their brain permeation and thereby develop the first anti-BMIC drug candidates. A drug that selectively kills BMICs can potentially be used in combination with conventional treatments for lung, breast, and melanoma tumors to prevent metastatic brain cancers.