We aim to find better ways to cure leukemia.

Relapse and dose-limiting toxicities are major therapeutic challenges in acute myelogenous leukemia (AML) given the current standard of care. The difficulty in treating AML is thought to arise from a chemoresistant subpopulation of leukemia stem cells that are capable of reinitiating disease. When patients are treated with chemotherapy, leukemia stem cells survive and allow the leukemia to re-grow, resulting in relapse. Dr. Guzman leads a research program focused on the development of therapeutic strategies for targeting leukemic stem cells. In close collaboration with physicians and industry, her research has resulted in the translation of laboratory findings into two phase 1 clinical trials. She collaborates with a multidisciplinary team of physicians, medicinal chemists, and genome scientists to develop the next generation of anti-leukemia stem cell therapies.

Drug discovery efforts at targeting leukemia stem cells.

The current standard of care in AML has remained largely unchanged for the past several decades. Patients undergo two phases of therapy termed "induction" and "consolidation". Induction therapy typically involves treatment with cytarabine (Ara-C) and anthracylines, where the goal is to reduce AML to undetectable levels. As most patients will relapse without further treatment, consolidation therapy aims to eliminate any residual disease. However, cytarabine and anthracyclines act mainly on dividing cells. We have shown that leukemia stem cells (LSCs) exist in non-dividing state and therefore resist these drugs. Thus, new drugs are urgently needed that capitalize on other properties of LSCs. Dr. Guzman was the first to show that LSCs depend on the pro-survival transcription factor, NFkappaB, for their function and developed NFkappaB-targeted therapies. One of these therapies, based on a pharmacologically superior derivative of the natural product parthenolide, is currently in phase I clinical trials in the United Kingdom. The collaborative environment of Weill Cornell/New York Presbyterian Hospital allows our laboratory to work closely with clinicians, medicinal chemists, and genome scientists to develop the next generation of drugs designed to target leukemia stem cells.

Improving methodologies to predict whether novel therapies will ablate myeloid leukemia stem cells.

Collaborators: Dr. Gail Roboz (Weill Cornell); Dr. Duane Hassane (Weill Cornell).
We propose that new therapies should center around new therapeutic endpoints such as the ablation of chemoresistant populations of LSCs. To achieve this goal, we hypothesize that LSCs are frequently present during remission at that they should be targeted during consolidation therapy. We aim to advance the targeting of LSCs and reduction of relapse by: (i) determining whether ex vivo treatments of LSCs more realistically reflect therapeutic outcome in patients compared to AML blast populations; (ii) defining the gene expression signatures of drug sensitivity and drug resistance of LSCs to identify better therapies; and (iii) identifying cell lines that best mimic the chemosensitivity of LSCs to have a readily available LSC surrogate in drug screens.

A role for elevated autophagy in survival and chemoresistance of leukemia stem cells.

We propose to determine whether autophagy plays a role in the survival and chemoresistance of LSCs. The evaluation of autophagy as a mediator of LSC chemoresistance and relapse is critical towards better delineating the unique features of LSCs that can be capitalized upon towards improving AML therapy. This project will address whether autophagy represents a feasible therapeutic target and/or sensitizes LSCs to induction therapy, diminishing the likelihood of relapse.

Genomic and epigenomic characterization of the drug resistance in acute myelogenous leukemia stem cells.

The overall goal of this project is to understand the mechanisms that lead to leukemia stem cell (LSC) chemoresistance in order to optimize the selection and the identification of drugs that can ablate LSCs that drive leukemia relapse. We are investigating the features unique genomic and epigenomic properties of LSCs that contribute to their chemoresistance to different drugs and characterizing such properties, would allow to find the Achilles’ heel of LSCs

Heat shock protein inhibitors to target AML stem cells.

In collaboration with Dr. Chiosis’ Lab at MSKCC we are investigating the role of heat shock proteins (HSPs) in AML stem and progenitor cells. We are using pharmacological and genomic approaches to interfere with the function of HSPs to determine their contribution to survival and chemoresistance of LSCs.

Natural products to target AML stem cells.

Our group is collaborating with different groups to investigate the potential of natural products for targeting LSCs. These efforts include interactions with Dr. Stefano Rivella’s group to investigate the effect of cranberry extracts. Dr. Peter Crooks and Cesar Compadre (University of Arkansas) investigating sesquiterpene lactones and combrestatin analogs, and the Drs. Michael Ballick and James Miller (New York Botanical Gardens) to identify medicinal plants that have potent effects against LSCs.