The Kaufmann laboratory studies what happens when cancer cells are treated with putative anticancer drugs. The resulting investigations focus on two major questions: 1) what is the biochemical basis for cell killing when it occurs, and 2) what can happen to cancer cells to make them resistant to the drugs? Within the context of these broad questions, the lab applies a wide range of biochemistry, cell biology, and molecular biology techniques to a series of projects.

Previous studies from this laboratory provided some of the first biochemical evidence that anticancer drugs induce apoptosis in susceptible cells, that selective protein degradation occurs during this process, and that intracellular cysteine proteases called caspases contribute to this degradation. Current studies are focused on the pathways that lead to caspase activation and the mechanisms that regulate these pathways. These studies include i) examination of Bcl-2 family member interactions and factors that influence them, including individual sequence variation; ii) an attempt to identify and characterize kinases that phosphorylate apoptotic pathway components; and iii) evaluation of small molecule antagonists of antiapoptotic pathway components as potential modulators of chemotherapy-induced apoptosis.

In attempting to better understand the changes that can help cells survive treatment with anticancer drugs, the Kaufmann laboratory studies mechanisms of resistance to topoisomerase poisons in model systems and in the clinical setting. Our earlier studies demonstrated the absence of topoisomerase II from the vast majority of blasts present in leukemic bone marrows. Additional experiments demonstrated constitutive expression of the ATP binding cassette transporter ABCG2 (also known as breast cancer resistance protein) as a major factor affecting sensitivity to certain camptothecin analogues. More recent studies have demonstrated that a DNA damage-induced signaling pathway involving the protein kinases ATR and Chk1 also modulates sensitivity to this class of agents. Current studies are focusing on the relationship between alterations in other DNA damage-induced signaling pathways and sensitivity to topoisomerase poisons.

In addition to studying mechanisms of anticancer drug resistance, the Kaufmann laboratory is involved in projects designed to overcome this resistance. In collaboration with research scientists at Mayo and elsewhere, along with members of the Phase I and Phase II clinical trials programs of the Mayo Clinic Cancer Center, we have previously evaluated the ability of a number of agents to modulate anticancer drug-induced killing. Agents that have previously been investigated in the Kaufmann laboratory include pyrazoloacridine, a dual topoisomerase I/topoisomerase II inhibitor that diminishes repair of platinum-DNA adducts; flavopiridol, a cyclin-dependent kinase inhibitor that enhances cisplatin accumulation and cytotoxicity in a wide variety of cancer cells; CI-1033 and lapatinib, tyrosine kinase inhibitors that modulate the uptake of camptothecin analogues in ABG2-expressing cancer cells; and adaphostin, a tyrphostin that enhances the cytotoxicity of the Bcr/abl kinase inhibitor imatinib mesylate. Current efforts are focused primarily on inhibitors of the ATR/Chk1 pathway and PI3 kinase/Akt/mTOR pathways.