On April 2, 2019 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported its new preclinical data across its franchise of selective cyclin-dependent kinase 7 (CDK7) inhibitors at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Atlanta (Press release, Syros Pharmaceuticals, APR 2, 2019, View Source [SID1234534930]). New data on SY-1365, a first-in-class selective CDK7 inhibitor currently in a Phase 1 clinical trial, suggest that RB pathway alterations are predictive of response in preclinical models of high-grade ovarian cancer (HGOC) and support the ongoing clinical investigation of SY-1365 in patient populations enriched for RB pathway alterations. New preclinical data on SY-5609, a selective oral CDK7 inhibitor, demonstrate broad anti-tumor activity in preclinical models of triple-negative breast cancer (TNBC) and ovarian cancer.

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"The new data on SY-1365 and SY-5609 further demonstrate our leadership in selective CDK7 inhibition, which we believe represents a potentially transformative targeted approach for many difficult-to-treat cancers," said Eric R. Olson, Ph.D., Syros’ Chief Scientific Officer. "The data highlight our ability to discover highly selective small molecule inhibitors of CDK7, a target that has been historically difficult to drug selectively, as well as to identify potential patient selection strategies to enable targeted and efficient clinical development. We remain focused on executing on the ongoing Phase 1 trial evaluating SY-1365 in select ovarian and breast cancer patient populations that we believe are most likely to respond. Meanwhile, we also continue to advance SY-5609, our highly selective and potent oral CDK7 inhibitor, toward a Phase 1 study. Together, we believe SY-1365 and SY-5609 could make for a powerful CDK7 franchise with the potential to provide a profound benefit for patients."

RB Alterations Predictive of Response to SY-1365 in Preclinical Models
Researchers from Syros evaluated tumor growth inhibition in a panel of HGOC patient derived xenograft (PDX) models, including both high-grade serous ovarian cancer (HGSOC) and clear cell ovarian cancer, to determine whether RB pathway alterations predict response to treatment with SY-1365. RB pathway alterations are present in 67 percent of HGSOC patients, according to The Cancer Genome Atlas analysis. In Syros’ study, RB pathway alterations were prospectively defined per The Cancer Genome Atlas criteria – including RB1 deletion or mutation, CDKN2A downregulation or deletion, CCNE1 amplification, CCND1 amplification, or CCND2 upregulation.

These data show that:

Ninety percent (9 of 10) of the PDX models with RB pathway alterations responded to treatment with SY-1365.
Forty percent (6 of 15) of the PDX models without prospectively defined RB alterations responded to treatment with SY-1365, suggesting the presence of other undetected RB pathway changes or alternative mechanisms, including transcriptional regulation, conferring sensitivity to SY-1365.
Overall, Syros believes these results support the ongoing development of SY-1365 in patient populations, including HGSOC and CDK4/6-inhibitor resistant hormone receptor-positive (HR+) breast cancer, that are enriched for RB pathway alterations, as well as the evaluation of these alterations as potential biomarkers of response to SY-1365.

Syros is currently conducting a Phase 1 clinical trial assessing the safety and efficacy of SY-1365 as a single agent and in combination with standard-of-care therapies in multiple ovarian and breast cancer patient populations. The trial includes cohorts evaluating SY-1365 as a single agent in patients with relapsed ovarian clear cell cancer; as a single agent in HGSOC patients who have had three or more prior lines of therapy; in combination with carboplatin in HGSOC patients who have had one or more prior lines of therapy; in combination with fulvestrant in HR+ breast cancer patients who are resistant to treatment with a CDK4/6 inhibitor; and as a single agent in patients with solid tumors accessible for biopsy. Syros expects to report initial clinical data from the dose expansion portion of the trial in the fourth quarter of 2019. Additional details about the trial can be found using the identifier NCT03134638 at www.clinicaltrials.gov.

SY-5609 Demonstrates Selectivity, Potency and Anti-Tumor Activity Preclinically
Researchers from Syros conducted a series of preclinical studies to characterize the in vitro and in vivo profile of SY-5609. The data show that SY-5609:

Demonstrated 13,000- to 49,000-fold greater selectivity for CDK7 over other CDK family members, including CDK2, CDK9 and CDK12.
Induced robust tumor growth inhibition effects and cell cycle arrest in TNBC and ovarian cancer cell lines at low nanomolar drug concentrations, with apoptosis demonstrated only in the TNBC and ovarian cancer models, but not in non-cancerous cells.
Significantly impacted tumor growth in vivo, with complete regressions observed with SY-5609 as a monotherapy in multiple TNBC and ovarian cancer cell line xenograft models at doses below the maximum tolerated dose.
Demonstrated substantial tumor growth inhibition in multiple TNBC and ovarian cancer PDX models, with minimum weight loss observed.
Led to decreases in CDK7 downstream protein markers, including MCL1, in treated tumor tissue, confirming CDK7 inhibition in vivo.
Syros is currently advancing SY-5609 through investigational new drug application enabling studies, with a Phase 1 oncology trial expected to begin in early 2020.

The posters presented at AACR (Free AACR Whitepaper) are now available on the Publications and Abstracts section of the Syros website at www.syros.com.