Our laboratory research program focuses on the study and evaluation of novel anticancer agents, with an emphasis on those with novel molecular targets. Our three areas of primary emphasis are:
- Molecular mechanism of action studies. A current example involves defining the novel mechanism of an investigational new agent that selectively induces specific cytochrome P450 isoforms directly in some (but not all) tumor cells, and defining the nature of subsequent DNA damage and damage response leading to cell death.
- Preclinical and clinical pharmacologic evaluation of new agents. We conduct extensive metabolism studies to define metabolic pathways prior to clinical trials and pharmacokinetic studies of new agents in preclinical and clinical trials settings.
- Pharmacogenetic studies. We investigate the role of inheritance in variation of responses to anticancer agents by genotyping patients for the presence of functional polymorphisms in those gene protein products. The mechanism of action studies encompass a number of laboratory methodologies including determination of molecular targets in tumor cells using human tumor cell lines, determination of cellular effects with an emphasis on DNA damage and cellular responses, and molecular methodologies including regulation of gene expression and induction, protein expression and function, and mechanisms of resistance. Metabolism studies utilize methods such as cDNA expressed drug metabolizing enzymes, selective inhibitors and inducers and human liver panel studies. For pharmacokinetic studies, drugs are analyzed by hplc, and lc/ms/ms, and pharmacokinetic parameters determined with a variety of computer software programs. For pharmacogenetic studies, we develop and implement genotyping assays using a variety of techniques.
Research available in our laboratory consists, then, of a relatively complete program of cancer pharmacology ranging molecular mechanism of action studies to clinical pharmacologic and pharmacogenetic studies in cancer patients.