Patient Specific Drug Combinations Improve AML Treatment

MedicalResearch.com Interview with:
Jeffrey Tyner, Ph.D.
Assistant Professor in Cell, Developmental and Cancer Biology at the Oregon Health & Science University School of Medicine and researcher and OHSU Knight Cancer Institute
Stephen Kurtz, Ph.D.
Research Assistant Professor at the Oregon Health & Science University School of Medicine Leukemia Center and researcher
OHSU Knight Cancer Institute

What is the background for this study? What are the main findings? 

Dr. Tyner: This study was one of many resulting from the ‘Beat AML’ initiative. Acute myeloid leukemia (AML) is a complex form of leukemia; less than 25 percent of newly diagnosed AML patients survive beyond five years. Led by the Knight Cancer Institute at Oregon Health & Science University and The Leukemia & Lymphoma Society (LLS), Beat AML brings together academic health centers and biopharmaceutical companies to accelerate discoveries to improve outcomes for patients with acute myeloid leukemia.

In this study, by using a unique method to test drugs used together, we identified drug combinations that are active against leukemia cells in a patient-specific manner.

Dr. Kurtz: For background, the intratumoral heterogeneity of AML and other hematologic malignancies presents a challenge in developing effective single-agent targeted treatments. With the goal of identifying new therapeutic combinations for AML and other hematologic malignancies, we assessed the sensitivity of primary patient samples to various drug combinations using an ex vivo functional platform.

The sensitivities of drug combinations across AML, ALL, CLL, CML or other MDS/MPN specimens are displayed in a heat map (Figure 1). For each combination, we compared the combination ratio of each individual specimen to the median combination ratio across all specimens tested; cases with a combination ratio value less than 20% of the median were considered hypersensitive to that combination. We calculated the percentage of cases that were sensitive to each combination within the diagnostic subsets and subsets with the most frequent sensitivity to a drug combination are indicated on the heat map.

As one example, combinations of two kinase inhibitors that included the p38MAPK inhibitor, doramapimod, were generally more effective on AML and CLL samples than other diagnostic subsets.

The data suggests that specific drug combinations formed either with two kinase inhibitors or with two compounds from different drug classes are effective in a patient-specific manner with enrichment for certain drug pairs within specific diagnostic subsets.

What should clinicians and patients take away from your report? 

Dr. Kurtz: While a secondary evaluation is necessary to validate the initial observation of sensitivity, linking this methodology with genetic attributes for patient samples will identify effective combinations of targeted agents and add therapeutic options for AML treatment.

What recommendations do you have for future research as a result of this study?

 Dr. Kurtz: The next step is to link these findings with the gene alterations that make cancer cells sensitive to the drug combinations. Eventually, we’d like to use those results to design clinical trials to help patients more directly.

 Dr. Tyner: We believe industry collaborations like Beat AML are key to better understanding the complex disease. As the number of collaborators increases, so too will the variety of approaches treatment exploration can take moving forward including testing how pairs of drugs might work better in stopping some versions of the disease.

Of the 27 potential treatments derived from Beat AML under analysis, 20 are already in clinical trials for other diseases; if these drug compounds show promise in treating AML, they have the potential for a faster approval process. 

Citation: Presented at the 57th American Society of Hematology

Identification of Effective Targeted Drug Combinations Using Functional Ex VivoScreening of Primary Patient Specimens

Chemical Biology and Experimental Therapeutics
Program: Oral and Poster Abstracts
Type: Oral Session: 802. Chemical Biology and Experimental Therapeutics
Monday, December 7, 2015: 4:30 PM

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Jeffrey Tyner, Ph.D., & Stephen Kurtz, Ph.D. (2015). Patient Specific Drug Combinations Improve AML Treatment 

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