Cancer Signaling and Metabolism
- Identifying and targeting metabolic weakness of triple negative breast cancer
- Understanding how cancer cell signaling impacts cell metabolism
- Controlling abberant cancer signaling and metabolism through the development and characterization of new drug-like small molecules
We seek to understand how cell signaling and metabolism are altered in cancer and to use that information to devise new therapeutic strategies. We use whatever approaches are required, whether protein biochemistry, high throughput screening, or genetics in model organisms, to advance our quest.
- Targeting molecular alterations that drive triple negative breast cancer growth
TNBC is a poorly understood but malignant type of breast cancer that disproportionately affects younger women and African-American women. There are currently no targeted therapies for TNBC but they are desperately needed. We have been characterizing molecular alterations in cell signaling and metabolic pathways that contribute to TNBC cell growth. We utilize cell line models and human tumor xenografts as model systems to developing new therapeutic approaches for this malignant breast cancer subtype. Our recent work has identified a metabolic weakness of TNBC and we are currently testing whether existing drugs that alter this pathway are active against this disease in cell line and xenograft models. In addition, we screen small molecule libraries to identify new lead compounds targeting vulnerable pathways in breast cancer.
- How do signaling pathways that drive cancer cell growth alter cellular metabolism to support tumor growth?
We have identified a novel link between growth factor signaling and nucleotide biosynthesis. Proliferating cells such as cancer cells have an elevated requirement for nucleotides. Rate-limited enzymes in nucleotide biosynthesis, IMPDH and CTPS, can reversibly polymerize under conditions of nucleotide deficit. We hypothesize that this assembly enhances nucleotide biosynthesis in an attempt to restore nucleotide levels and may be relevant in supporting the growth of cancer cells. Importantly, we have identified a kinase as a regulator of the polymerization of these enzymes. Furthermore we have identified novel inhibitors of this kinase that might represent a way to starve cancer cells of nucleotides and halt their growth. We are working at all levels; from studying the biochemistry of purified proteins to their function in genetically engineered organisms to address these fundamental questions:
- In what biological contexts is polymerization of IMPDH and CTPS important?
- How is their assembly regulated?
- What other components co-assemble with IMPDH and CTPS?
- How does assembly affect their catalytic activity?
The answers to these questions will reveal how cellular signaling pathways can influence cell metabolism and may suggest new therapeutic approaches in cancer.