On May 4, 2017 Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of disease-driving genes, reported new data generated using its gene control platform, including the discovery of 14 new drug targets in triple negative breast cancer (Press release, Syros Pharmaceuticals, MAY 4, 2017, View Source [SID1234518828]). These discoveries demonstrate the power of Syros’ pioneering approach for systematically analyzing regulatory regions of the genome to identify novel targets for defined subsets of patients with diseases that have eluded other genomics-based approaches. These data were presented at the IMPAKT 2017 Breast Cancer Conference in Brussels, Belgium. Schedule your 30 min Free 1stOncology Demo! "Targeted drug discovery in cancer has focused on mutations in protein-coding regions of the genome, and while some cancers have been well served by this approach, many other cancers, including triple negative breast cancer, remain unaddressed," said Eric Olson, Ph.D., Chief Scientific Officer of Syros. "By analyzing the non-coding regulatory region of the genome of tumor cells, we have uncovered new targets in subsets of triple negative breast cancer. Our focus on the regulatory genome, coupled with our expertise in drugging transcriptional targets to control the expression of genes, positions us to develop a new wave of genomic-based medicines for patients with diseases that have remained beyond the reach of other targeted approaches."
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Using its proprietary gene control platform to analyze the regulatory genomes from 43 breast cancer patients’ tissue samples, Syros scientists identified highly specialized regions of non-coding regulatory DNA, known as super-enhancers, that drive the expression of genes critical for tumor growth and survival in defined subsets of breast cancer patients. Analysis of the super-enhancers and their associated genes revealed:
Known cancer drivers and patient subsets, with HER2+ patients having a super-enhancer associated with the HER2 gene and ER+ patients having a super-enhancer associated with the ESR1 gene, providing validation that super-enhancer analysis can be used to identify clinically relevant disease drivers in defined patient subsets.
Enhancer-linked genes that were validated as essential for triple negative tumor cell proliferation by CRISPR-mediated gene disruption.
Of those genes, 14 code for newly identified drug targets for triple negative breast cancer across a range of druggable target types, including enzymes, surface receptors, and signaling and metabolic proteins.
A super-enhancer associated with the RARA gene that is predictive of response to SY-1425, a first-in-class selective retinoic acid receptor alpha (RARα) agonist, in multiple preclinical models of breast cancer, including those resistant to treatment with standard-of-care therapies. Notably, the RARA super-enhancer is present across known subtypes of breast cancer, and Syros estimates it is present in about 35 percent of breast cancer patients. SY-1425 is currently in a Phase 2 clinical trial for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who are positive for biomarkers for super-enhancers linked to RARA pathway-associated genes, including RARA and IRF8. Upon achieving clinical proof-of-concept in that trial, Syros plans to expand development of SY-1425 into genomically defined subsets of breast cancer patients.
Syros’ drug discovery and development platform is the first to focus solely on the regulatory genome to systematically and efficiently identify disease-causing alterations in gene expression and create medicines to selectively target transcription to control the expression of genes with the aim of treating cancer, as well as autoimmune and rare genetic diseases. Using its platform, Syros is advancing a growing pipeline of drug candidates, including SY-1425 and SY-1365, a first-in-class selective inhibitor of cyclin-dependent kinase 7 (CDK7), that is on track to begin a Phase 1 clinical trial in the second quarter of this year in patients with transcriptionally dependent solid tumors, including triple negative breast, small cell lung and ovarian cancers.