AML cells
Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.
The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.
The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.
And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.
Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.
In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.
The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.
The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.
The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.
Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.
The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.
DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.
In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
