Epigenetic inhibitors have demonstrated tumor efficacy by modulating genes involved in growth, proliferation, and invasiveness in hematological malignancies like AML. Preclinical evidences suggest therapeutic benefit by combining epigenetic drugs along with other therapeutics like JAK2 inhibitors. However, there is a huge unmet need to understand the disparities in response at the individual patient level.
We developed a novel functional assay based platform called CANscript™ to predict the efficacy of anticancer drugs in clinic, which mimics patient tumor microenvironment (Majumder B et al., Nature Communications, 2015). Utilizing samples from AML patients we interrogated response to HDAC and DNA MTase inhibitors by assessing tumor viability, proliferation, morphology, and death in this platform. To elucidate the mechanisms of response, we delineated the pharmacodynamic and pathway modulation by immunohistochemistry and mRNA microarray.
Thirty-two AML patients samples were analyzed in this platform. HDAC and DNA MTase blockade resulted antitumor response, which was demonstrated by differential and quantitatively distinct patterns of target engagement. mRNAs and pathway specific protein expression profiling is suggestive of JAK2 pathway deregulation in many of the non-responders. Treatment with JAK2 inhibitor in this cohort led to efficacy in 40% of these non-responders, suggesting the critical role of this pathway. Interestingly, unique JAK2 signatures associated with single agent vs. combination therapy was observed (10%), hinting at functionally distinct mechanisms of antitumor effects at individualized levels.
These findings demonstrate the utility of this ex vivo platform to predict therapeutic response of epigenetic modulators at the individual patient tumor. It also highlights that, within a contextually heterogeneous framework, distinct mechanisms orchestrate response to HDAC and DNA MTase inhibitors as a single agent or in combination with JAK2 inhibitors. Insights gained from these findings can re-shape our strategic thinking of drug selection for the treatment of AML.
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G. Babu: Independent consultant and full time employee of Kidwai Memorial Institute of Oncology, scientific and clinical advisory board of Mitra Biotech and equity in this organization. All other authors have declared no conflicts of interest.