The Douglass Lab combines the tools of organic chemistry, biochemistry and computational biology to overcome the urgent problem of multi-drug resistance (MDR) in cancer. It has been estimated that MDR is responsible for 90% of treatment failures in metastatic cancer and methods to overcome MDR could have a broad-ranging impact in the clinic(J. Pathol. 2005, 205, 275). The major contributors to MDR are drug efflux and metabolism enzymes (Figure 1) which contribute to resistance of nearly all FDA-approved cancer drugs (Nat. Rev. Cancer 2018, 18, 452).
Traditional 1-drug/1-target approaches to drug-development are insufficient to tackle MDR as individual drugs are often targeted by >10 MDR-enzymes and individual MDR-enzymes can target hundreds of drugs. We believe this multi-factorial problem is well suited to the tools of data-science and chemical biology. Our laboratory has three programs that tackle MDR from distinct but complementary perspectives:
- Our Organic Chemistry Program focuses on on making new drugs by modifying clinical drugs to be resistant to MDR efflux or metabolism.
- Our Biochemistry Chemistry Program focuses on enabling drug-repurposing for MDR-tumors by measuring kinetic parameters (kcat, Km) for individual drug/resistant-gene pairs. This data can be used to create ranked-lists of approved drugs for an individual cancers that display an MDR-phenotype.
- Our Data Science Program focuses on enabling drug-repurposing for all tumors by creating drug-sensitivity “blue-print” for individual cancers. This work combines MDR-factors with other biological features that predict drug-sensitivity (e.g. proliferative capacity, apoptotic-activity, etc.) to match drugs to patients even in the absence of a clear MDR-phenotype.