Of the 1.4 million Americans diagnosed with cancer this year, roughly 600,000 will die of this group of diseases. If current chemotherapy or immunotherapy were effective, these patients would be cured of their neoplasms. Our laboratory is attempting to gain insight into the limited efficacy of current therapies by investigating the biochemical basis for killing by effective chemotherapeutic agents and cytotoxic lymphocytes as well as the mechanisms by neoplastic cells evade this killing.
Apoptosis (programmed cell death) is a distinct form of cell death that occurs under a variety of physiological and pathological conditions. Building on earlier observations that a variety of chemotherapeutic agents induce apoptosis in susceptible cell types, members of my laboratory are investigating how the signaling by various components of apoptotic pathways is affected by changes in phosphorylation and other posttranslational modifications. At the same time, other members of my laboratory are using topoisomerase I poisons, which are used to treat a number of common cancers, as prototypic drugs to investigate changes further upstream that determine whether anticancer drugs are able to interact with their targets and trigger the signaling required to activate the cell death process. Finally, in conjunction with other members of the Developmental Therapeutics Program of the Mayo Clinic Cancer Center, we are examining the cytotoxic action of a number of novel anticancer agents in preclinical model systems and, in some cases, in the context of phase I and phase II clinical trials.