Cytotoxic Action of Novel Antineoplastic 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, along with members of the phase I and phase II clinical trials programs in the Developmental Therapeutics Program of the Mayo Clinic Cancer Center, Dr. Kaufmann's laboratory studies the action of promising investigational anticancer drugs in preclinical models or in the clinical setting, or both.

The goal of these studies is to improve understanding of individual anticancer drugs to the point that it's possible to identify tumors most likely to respond to them.

One major effort in our laboratory during the past decade focused on understanding mechanisms of action of farnesyltransferase (FT) inhibitors (FTIs), agents that have shown promising activity against acute myelogenous leukemia (AML) in older patients and against relapsed T-cell lymphomas.

These efforts showed that FTIs induce apoptosis through distinct mechanisms in lymphoma (inhibition of mitogen-activated kinase signaling) versus AML (inhibition of Rheb-mediated mTOR activation), providing new insight into potential mechanisms of resistance, as well.

Ongoing clinical studies related to these earlier effects include a phase II trial of tipifarnib in peripheral T-cell lymphoma and a separate trial in myeloproliferative neoplasms.

Other research efforts in the Anticancer Drug Action Lab included 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 + Chk1 inhibitors in acute myelogenous leukemia and gemcitabine + carboplatin + ATR inhibitors in such solid tumors as ovarian cancer.

Finally, our recent studies of a new class of agents called mTOR dual inhibitors have contributed to the clinical development of these agents. These studies build 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 more recent investigations showed that acute lymphoblastic leukemias (ALLs) are particularly sensitive to the next-generation mTOR inhibitors and also identified two pro-apoptotic BCL2 family members that are upregulated in malignant lymphocytes by these agents. This provided improved understanding of potential determinants of sensitivity or resistance and led to a clinical trial of TAK-228/MLN0128 in relapsed ALL.