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 gain-of-function mutations that occur in certain cancers; ii) identification and characterization of kinases that phosphorylate apoptotic pathway components; and iii) evaluation of small molecules that interact with pathway components to modulate chemotherapy-induced apoptosis.
The Kaufmann laboratory is also attempting to understand how anticancer agents engage the apoptotic machinery. These efforts focus on drugs that are used to treat ovarian cancer and hematological malignancies, including acute leukemias and lymphomas. Agents that are currently being studied include inhibitors of poly(ADP-ribose) polymerase (PARP), the mammalian target of rapamycin (mTOR), DNA topoisomerase I, checkpoint kinase I (Chk1) and the ubiquitin-proteasome pathway (e.g., bortezomib). In the case of PARP inhibitors, work from the Kaufmann laboratory has shown that these agents selectively kill BRCA1- and BRCA2-deficient cells by enhancing activation of an error-prone DNA repair pathway (the nonhomologous end-joining pathway), providing a mechanistic basis for the so-called synthetic lethality between PARP inhibition and loss of BRCA1/2. These observations provide important new insight into the conditions that must be met for PARP inhibitors to be used successfully to treat cancers. Studies to examine mechanisms of resistance to PARP inhibitors in laboratory models and clinical cancers are in progress. A similar in-depth approach is likewise being applied to the other classes of agents listed above.
In collaboration with members of the Phase I and Phase II clinical trials programs of the Mayo Clinic Cancer Center, along with clinical researchers elsewhere, the Kaufmann laboratory is helping translate the most promising of these preclinical studies into novel clinical trials. Treatments that have originated in the Kaufmann laboratory have included flavopiridol + cisplatin (tested in ovarian cancer), topotecan + lapatinib (tested in ovarian cancer), topotecan + carboplatin (being tested for relapsed AML through the Eastern Cooperative Oncology Group), cytarabine + MK-8776 (being tested in AML), and topotecan + veliparib (being tested in ovarian cancer at Mayo). Laboratory studies performed in conjunction with these trials are designed to i) determine whether the chemotherapeutic agents are having the intended biochemical effects in cancer cells and ii) better identify patients who are most likely to benefit from these treatments.