On December 10, 2016 Syros Pharmaceuticals (NASDAQ: SYRS) reported the presentation of new data on SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist, showing that SY-1425 inhibited tumor growth in multiple preclinical models of breast cancer driven by high levels of RARA gene expression (Press release, Syros Pharmaceuticals, DEC 10, 2016, View Source;p=irol-newsArticle&ID=2228847 [SID1234517024]). In these studies, SY-1425 showed significant anti-proliferative activity both as a single agent and in combination with standard-of-care breast cancer therapies in in vitro and in vivo models of breast cancer, including those resistant to existing treatments. These data were presented at the 39th Annual San Antonio Breast Cancer Symposium (SABCS).

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"Despite tremendous progress in treating certain types of breast cancer, two of the greatest remaining challenges are our ability to identify the right treatment for the right patient and cancer’s ability to become resistant to treatment," said Nancy Simonian, M.D., Chief Executive Officer of Syros. "The new data on SY-1425 show that we have the potential to address both these challenges for subsets of breast cancer patients whose disease is driven by abnormally high expression of the RARA gene."

The data presented at SABCS show that subsets of breast cancer patients’ tumors have a highly specialized region of regulatory DNA, known as a super-enhancer, that is associated with the RARA gene and drives high levels of RARA gene expression. In preclinical models of breast cancer, high RARA gene expression was shown to be predictive of response to treatment with SY-1425. The data highlight that SY-1425:

Inhibited tumor growth in breast cancer cell lines as well as cell line-derived xenograft and patient-derived xenograft models of breast cancer with high RARA gene expression, including models of HER2-positive breast cancer resistant to treatment with trastuzumab and ER-positive breast cancer resistant to hormonal therapies. By contrast, SY-1425 did not inhibit tumor growth in models of breast cancer with low RARA gene expression.
Reduced the expression of genes responsible for tumor growth in HER2-positive and ER-positive breast cancer cells with high RARA expression.
Increased the anti-tumor effects of standard-of-care therapies, including tamoxifen and palbociclib in ER-positive breast cancer cells with high RARA expression and lapatinib in HER2-positive breast cancer cells with high RARA expression.
These data support the potential clinical development of SY-1425 in genomically defined subsets of breast cancer patients.

SY-1425 is currently in a Phase 2 clinical trial in genomically defined subsets of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. Using its gene control platform, Syros discovered subsets of AML, MDS and breast cancer patients whose tumors have the super-enhancer associated with the RARA gene, which codes for the RARα transcription factor. The resulting over-expression of RARα locks the cells in an immature, undifferentiated and proliferative state. Treatment with SY-1425 in cancer cells with this super-enhancer promotes differentiation of these cells. Upon achieving clinical proof-of concept in AML and MDS, Syros plans to expand development of SY-1425 into genomically defined subsets of breast cancer patients.

SY-1425 is approved in Japan as Amnolake (tamibarotene) to treat relapsed or refractory APL, a form of AML that is driven by a fusion of the RARA gene with other genes. Syros in-licensed SY-1425 for development and commercialization in North America and Europe in cancer. Additional details about the ongoing Phase 2 trial in AML and MDS can be found using the identifier NCT02807558 at www.clinicaltrials.gov.