Sy-1425 (Tamibarotene), A Selective Rar Alpha Agonist, Shows Synergistic Anti-Tumor Activity With Hypomethylating Agents In A Biomarker Selected Subset Of Aml

In patients with acute myeloid leukemia (AML) (≥ 60 years) and myelodysplastic syndrome (MDS), the use of hypomethylating agents (HMAs) may extend survival, but cure rates are very low and new treatment approaches are needed. HMAs, such as azacitidine, work by inhibiting DNMT1, leading to depletion of DNA methylation in the tumor cells. Hypomethylation, in turn, leads to the re-expression of genes associated with differentiation and growth arrest. We have recently explored the potent and selective RARα agonist SY-1425 in a genomically defined subset of AML. SY-1425 binds to RARα and causes a transition from repression to strong activation of target genes, thus reprogramming the tumor cells toward terminal maturation in RARA-high AML models, supporting our recently initiated Phase 2 trial in a biomarker-selected subset of AML and MDS (NCT02807558). Based on potential mechanistic synergy, we evaluated SY-1425 in combination with HMAs and identified a synergistic anti-proliferative effect. In RARA-high AML cell lines, but not RARA-low, the combination of SY-1425 with either azacitidine or decitabine showed synergistic anti-proliferative effects on the cells, with combination indices less than 0.5 over a range of concentrations from 0.01 to 100nM of SY-1425 and 0.1 to 1µM of HMAs. SY-1425 and azacitidine were also co-administered to a disseminated patient-derived xenograft (PDX) mouse model of RARA-high AML. The combination demonstrated superior reduction of tumor burden vs either therapy alone, leading to deeper and more durable responses with less than 1% detectable tumor burden. A follow-up study in the RARA-high PDX model investigated different treatment schedules of SY-1425 and azacitidine over a period of 56 days, supporting a regimen that maximizes anti-tumor activity and tolerability. Mechanistic studies using RNA-seq and ChIP-seq in AML cell line models have revealed that while azacitidine had only moderate suppressive or activating effects over a broad set of genes, the addition of SY-1425 in RARA-high models resulted in strong and specific induction of genes bound by RARα. It is hypothesized that azacitidine acts to prime the tumor cells for reprogramming by SY-1425. The loss of methyl-cytosine residues following azacitidine treatment lowers the barrier to SY-1425 mediated gene induction. It was observed that the two agents work cooperatively to promote terminal differentiation and decrease proliferation of the AML tumor cells, with the potential for increased clinical benefit in a subset of AML defined by a RARA super-enhancer. Based on the largely non-overlapping clinical toxicity profiles of azacitidine and SY-1425, supported by the observed tolerability of the combination in preclinical models, these findings provide a strong rationale for a planned study of this combination in biomarker selected, newly diagnosed AML patients. Citation Format: Michael R. McKeown, Emily Lee, Chris Fiore, Matthew L. Eaton, Christian C. Fritz, Eric Olson. SY-1425 (tamibarotene), a selective RARα agonist, shows synergistic anti-tumor activity with hypomethylating agents in a biomarker selected subset of AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3085. doi:10.1158/1538-7445.AM2017-3085