Abstract 1187: Discovery of new AML and MDS patient subsets sensitive to the highly selective RARα agonist SY-1425 (tamibarotene) through super-enhancer analysis
Authors: McKeown Michael R. , Lee Emily , Fiore Chris , Eaton Matthew L. , Lopez Jeremy , Corces-Zimmerman Ryan , Majeti Ravindra , Fritz Christian , Olson Eric 
Published: July 2016

Abstract
Super-enhancers (SEs) are large, highly active chromatin regions that regulate key cell identity genes including oncogenes in malignant cells. Using our gene control platform, we identified SEs genome-wide in 60 primary AML patient samples to enable the discovery of novel tumor vulnerabilities. One of the SEs that showed a highly asymmetric distribution amongst patient samples was associated with the gene encoding the retinoic acid receptor alpha (RARα). We have discovered that the presence of a RARA SE is predictive for response of non- APL AML cell lines to the highly selective RARα agonist SY-1425. SY-1425 is a clinical stage RARα agonist with improved PK, potency, and selectivity over existing pan-retinoic acid agonists.
SY-1425 has sub-nanomolar potency on RARα, with 200-2000 fold selectivity over other RAR family members. SY-1425 treatment of AML cell lines containing a RARA SE results in 0.2-2 nanomolar EC50 anti-proliferative effects, whereas proliferation of cell lines without SEs are not affected. The RARA enhancer level (as measured by H3K27ac ChIP-seq) is well correlated with mRNA levels for RARα. Two patient derived xenograft models with high RARα mRNA show prolonged survival and tumor cell differentiation response to SY-1425, whereas two models with low RARα mRNA do not show a treatment effect. In contrast, treatment with the non-selective agonist ATRA fails to show a survival benefit in a RARα mRNA high model, presumably due to its lower agonist activity and its inferior PK.
RARα is a nuclear hormone receptor that acts as a transcriptional repressor when unliganded and as a transcriptional activator when bound by an agonist. SY-1425 treatment of SE containing AML cells shows a transcriptional response very similar to retinoid treatment of APL cells. Analysis of ex vivo treated primary AML cells as well as analysis of bone marrow and blood samples from SY-1425 treated patient derived xenograft models support an anti-proliferative and differentiation induction effect in cells containing the RARA SE but not in cells lacking the RARA SE. In addition to AML, a sub-population of MDS patient samples also contain elevated RARα mRNA levels, suggesting the potential utility of SY-1425 in this closely related indication.
In summary, using our gene control platform, we have identified subsets of non-APL AML and MDS who may respond to the selective RARa agonist, SY-1425. A phase 2 clinical study with SY-1425 is being planned in patients identified with a novel biomarker based on these findings.
Citation Format: Michael R. McKeown, Emily Lee, Chris Fiore, Matthew L. Eaton, Jeremy Lopez, Ryan Corces-Zimmerman, Ravindra Majeti, Christian Fritz, Eric Olson. Discovery of new AML and MDS patient subsets sensitive to the highly selective RARα agonist SY-1425 (tamibarotene) through super-enhancer analysis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1187.