Cytotoxic Action of Novel Anti-Neoplastic Agents

Dr. Kaufmann and his team in the Anticancer Drug Action Lab are studying the cytotoxic action of novel anti-neoplastic agents.

In collaboration with research scientists at Mayo Clinic and elsewhere, and along with members of the Experimental Therapeutics Program of the Mayo Clinic Comprehensive Cancer Center, Dr. Kaufmann's laboratory studies the action of promising investigational anti-cancer drugs in preclinical models, in the clinical setting or both.

The goal of these studies is to improve understanding of individual anti-cancer drugs to the point that it's possible to identify tumors most likely to respond to them. Two present research efforts in the Anticancer Drug Action Lab include examination of the action of PARP inhibitors and of inhibitors of the ATR/Chk1 pathway.

In particular, building on our lab's earlier studies showing that anti-neoplastic agents such as cytarabine (used in leukemia and lymphoma) and gemcitabine (used in solid tumors) activate the ATR/Chk1 DNA damage response pathway, we have explored the ability of Chk1 inhibitors, and more recently ATR inhibitors, to selectively sensitize cancer cells to cytarabine or gemcitabine. These studies have led to early-phase clinical trials of cytarabine plus Chk1 inhibitors in acute myelogenous leukemia and gemcitabine or carboplatin plus ATR inhibitors in such solid tumors as ovarian cancer.

More recently, our studies demonstrated that ATR and Chk1 inhibitors exhibit single-agent activity in preclinical models of acute leukemia and solid tumors. The pathways involved in engaging the apoptotic machinery vary from cell type to cell type and are still under active investigation.

Our earlier efforts also identified the cytotoxic mechanism for dual mTOR inhibitors such as MLN0128/TAK228 in susceptible lymphoid malignancies. These studies built on our earlier clinical trial that demonstrated unprecedented clinical activity of the mTOR inhibitor temsirolimus in relapsed mantle cell lymphoma, leading to regulatory approval of temsirolimus in Europe for this indication.

Our subsequent investigations showed that acute lymphoblastic leukemias (ALLs) are particularly sensitive to the next-generation mTOR inhibitors. We identified two pro-apoptotic BCL2 family members that are upregulated in malignant lymphocytes by these agents, providing improved understanding of potential determinants of sensitivity or resistance to these agents. Recent studies have led to identification of an agent that impacts the mTOR pathway but lacks the systemic toxicities of dual mTOR inhibitors, providing a potential new strategy for relapsed and refractory lymphoid malignancies.