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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

5920 - Identification of the rational combination of two epigenetic inhibitors therapy in refractory AML using patient tumor derived ex vivo platform.

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Pradip Majumder

Citation

Annals of Oncology (2018) 29 (suppl_8): viii649-viii669. 10.1093/annonc/mdy303

Authors

P.K. Majumder1, G. Babu2, C. Rajagowda2, S. Thiyagarajan3, M. Biswas4, P. Radhakrishnan1, P. Chaudhuri3, A. Chatterjee3

Author affiliations

  • 1 Cancer biology, Mitra Biotech, 01801 - Woburn/US
  • 2 Kidwai Memorial Institute Of Oncology, HCG Curie Centre of Oncology, 560029 - Bangalore/IN
  • 3 Cancer biology, Mitra Biotech, 560099 - Bangalore/IN
  • 4 Molecular Pathology, Mitra Biotech, 560029 - Bangalore/IN
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Resources

Abstract 5920

Background

Acute myeloid leukemia (AML) is a highly heterogenous hematological malignancy. Though there has been substantial progress in understanding of AML biology and identification of new therapeutic targets, treatment of AML has largely remained unchanged over the last couple of decades, with ∼40% patients not achieving remission with standard chemotherapies.

Methods

In this study, we employed an ex-vivo tumor explant model (CANscript™) to select a treatment course for AML patients. CANscript™ offers a comprehensive system that mimics patient tumor microenvironment. 31 AML patients tumors were analyzed to predict response to cytarabine. We next evaluated azacitidine and panobinostat alone and in combination, as alternate treatment regimens for cytarabine refractory tumors.

Results

More than 50% of the treated samples showed response to the combination therapy. In AML, frequent upregulation of DNA-methyltransferase enzymes (DNMTs) have been reported with poor survival. We assessed the level of DNMTs using RNAseq and methylation data (n = 100) from the TCGA database. Data indicated increased expression of DNMT and hyperacetylation of HDACs indicating mechanism of high responsiveness to treatment by epigenetic modulators in these tumors. We further noted hypomethylation of IFNGR1 and IFNGR2 genes in TCGA data suggesting activation of JAK/STAT pathway. Hypomethylation of several gene components of JAK-STAT pathway was correlated with an increased expression of these genes in RNAseq data. 8 out of 12 cytarabine refractory tumors were showed response of which 5 were non-responders to epigenetic modulators.

Conclusions

Taken together our data indicates that CANscript™ is capable in guiding optimal treatment selection for various classes of agents including novel targeted therapies.

Clinical trial identification

Legal entity responsible for the study

Mitra Biotech and Kidwai Memorial of Institute of Oncology.

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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