1695P - Deciphering the antitumor efficacy and mechanistic delineation of epigenetic inhibitors in AML using patient tumor derived ex vivo phenotypic assay...

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Leukaemia
Translational Research
Presenter Pradip Majumder
Citation Annals of Oncology (2017) 28 (suppl_5): v573-v594. 10.1093/annonc/mdx390
Authors P.K. Majumder1, P. Radhakrishnan1, S. Thiagarajan2, M. Biswas3, D.G. Malhotra3, B. Ulaganathan1, B. Majumder2, G. Babu4
  • 1Cancer Biology, Mitra Biotech, 01801 - Woburn/US
  • 2Cancer Biology, Mitra Biotech, 560099 - Bangalore/IN
  • 3Molecular Pathology, Mitra Biotech, 560099 - Bangalore/IN
  • 4Medical Oncology, Kidwai cancer institute, 560029 - Bengaluru/IN

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

Not Applicable

Legal entity responsible for the study

Mitra RxDx

Funding

Mitra RxDx

Disclosure

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.