1. Elucidate the functional interplay between the nucleoside salvage pathway (NSP) and DNA replication stress in hematopoiesis, and adaptive immunity. The NSP is essential for activating pro-drugs widely used in cancer and viral infections. However, its biological function remains unknown, limiting the development of new diagnostic and therapeutic applications. Ongoing projects in our lab use new genetic, imaging and pharmacological approaches to gain a detailed mechanistic understanding of nucleoside salvage metabolism in hematopoiesis and adaptive immunity.
2. Targeting nucleotide metabolism and DNA replication stress in cancer. In tumor cells, rapid proliferation, aneuploidy and genomic instability increase the demand for nucleotides. We hypothesize that the increased demand for nucleotides represents a metabolic liability, which can be targeted therapeutically by a new class of kinase inhibitors developed by our group. The efficacy of these therapeutic agents is being evaluated in aggressive malignancies that are resistant to both conventional and targeted therapies.
3. PET probe development. We seek to identify key biochemical and metabolic pathways in lymphocytes and cancer cells that are quantifiable using PET imaging. We have already demonstrated examples of these approaches and how they can be implemented in the clinic. We are also developing PET assays to monitor cell-based therapies, including those using T lymphocytes and stem cells. Such tools may eventually enable clinicians to follow transplanted cells and determine if they survive and engraft, home to areas of disease, and are able to reestablish the activity needed to counteract disease.
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