Combination Approach May Prevent Drug Resistance in Hematologic Malignancies

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The right combo at a critical point in tumor evolution may stop progression of heterogeneous tumors.
The right combo at a critical point in tumor evolution may stop progression of heterogeneous tumors.

Treating hematologic malignancies with a combination of drugs early in the course of therapy, rather than waiting for a patient to relapse, may prevent the development of drug resistance, according to Douglas Lauffenburger, PhD, professor in the Department of Biological Engineering and the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology in Cambridge, MA.

Dr. Lauffenburger presented data from his research at the American Association for Cancer Research special conference, Hematologic Malignancies: Translating Discoveries to Novel Therapies, held in late September in Philadelphia, PA.

“The goal that we've been working toward is learning how to address tumor heterogeneity, which is widely appreciated as being involved in the difficulties of treating tumors,” Dr. Lauffenburger said.

Using both experimental approaches and computational methods, Dr. Lauffenburger's team has investigated BCR-ABL–associated malignancies such as chronic myelogenous leukemia (CML) and Philadelphia-like acute lymphoblastic leukemia (ALL) using mouse and human cell cultures.

“Our most interesting findings are two-fold,” Dr. Lauffenburger said. “First, we show that treatment of these leukemia cells with kinase inhibitors not directed against BCR-ABL can nonetheless show effectiveness against BCR-ABL–driven proliferation. We believe these agents may be working against different subpopulations of a heterogeneous tumor.”

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“Second,” Dr. Lauffenburger continued, “we show that treatment of leukemia cells with BCR-ABL–directed drugs such as imatinib and dasatinib appears to sensitize against the MET-directed drugs for a time window shortly after the original treatment, but before longer-term dose-escalation with BCR-ABL–directed drugs.”

With the ability to sequence both DNA and RNA, Dr. Lauffenburger explained, the potential exists to characterize tumor heterogeneity and determine what subpopulations and clones might emerge after initial treatment with a particular drug.

Knowing the subpopulations in the original heterogeneous tumor and using combination therapy early—perhaps only 1 or 2 weeks after initial treatment—might kill off enough remaining cells so that longer-term drug-induced mutations would not occur.

 “From our studies, we found that, for example, it would be ideal to treat an ALL patient with dasatinib followed by crizotinib/foretinib for synergy during the early stages of clonal evolution of the patient's tumor, rather than treating only with dasatinib and waiting until the patient has relapsed,” Dr. Lauffenburger said.

He noted that the next step in research would be to undertake sequencing of the tumor subpopulation time courses and their different driving factors and thereby predict the best drug combinations and sequences, which would then be tested in animal models.

 “That information is underutilized because it's highly complex,” Dr. Lauffenburger explained, “but with the right mathematical analysis, we ought to be able to predict what drug combination will give the most beneficial outcome.”

Commenting on this research, Kenneth C. Anderson, MD, conference chair, said, “This is coming along at the best time because there is an understanding of the clonal heterogeneity and its progression and ways that we might interrupt it.”

Dr. Lauffenburger agreed, saying, “We're trying to get ahead of the tumor.”

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