On December 7, 2018 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported new preclinical data on SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor, showing that it inhibits tumor cell growth in hormone receptor-positive (HR-positive) breast cancer cell lines that are resistant to treatment with CDK4/6 inhibitors and that it has synergistic activity in combination with fulvestrant in these treatment-resistant cells (Press release, Syros Pharmaceuticals, DEC 7, 2018, View Source [SID1234531956]). These data are being presented by Syros’ collaborators from Dana-Farber Cancer Institute at the San Antonio Breast Cancer Symposium (SABCS).
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"While CDK4/6 inhibitors have emerged as an important class of treatments for HR-positive metastatic breast cancer, patients eventually develop resistance," said Rinath M. Jeselsohn, M.D., Instructor in Medicine at Dana-Farber and principal investigator of the research presentation. "These data shed light on potential mechanisms behind resistance to CDK4/6 inhibitors, pointing to CDK7 as one of the genes critical to the growth of treatment-resistant HR-positive breast cancer cells and selective CDK7 inhibition as a promising new approach for the treatment of HR-positive breast cancer. I look forward to the continuing to evaluate SY-1365 in the ongoing Phase 1 trial focused on breast and ovarian cancers."
Researchers from Dana-Farber characterized an HR-positive breast cancer cell line that is resistant to treatment with CDK4/6 inhibitors, and they demonstrated that these cells have alterations in the RB-pathway, including loss of the retinoblastoma (Rb) protein, higher levels of p107, CDK2 and cyclin E2, and lower levels of the estrogen receptor.
The aim of this study was to identify genes critical for the growth and survival of these cells by evaluating both resistant and sensitive cell lines. The researchers also tested SY-1365 in these resistant cell lines as a single agent and in combination with fulvestrant, an estrogen receptor degrader. The data, highlighted in a Spotlight poster discussion session, show that:
CDK7 and ESR1 are critical for in vitro cell growth in both CDK4/6 inhibitor-sensitive and CDK4/6 inhibitor-resistant cells.
SY-1365 significantly arrests cell cycle progression and reduces the expression of cancer-promoting genes in both CDK4/6 inhibitor-sensitive and -resistant cell lines.
SY-1365 in combination with fulvestrant demonstrates synergistic activity in CDK4/6 inhibitor resistant cells.
"We are encouraged by these new preclinical data, which speak both to the importance of CDK7 inhibition in HR-positive breast cancer and to the specific potential of this approach in patients who develop resistance to CDK 4/6 inhibitors.," said David Roth, M.D., Chief Medical Officer of Syros. "We are particularly pleased by the data for SY-1365 in combination with fulvestrant, which demonstrate synergistic activity in CDK4/6 inhibitor-resistant HR-positive breast cancer cells. These data support the ongoing clinical evaluation of SY-1365 in combination with fulvestrant in HR-positive breast cancer patients who progress after treatment with a CDK 4/6 inhibitor. We are actively enrolling patients in the Phase 1 trial and are committed to exploring the full potential of CDK7 inhibition with SY-1365 for people with difficult-to-treat cancers."
The ongoing Phase 1 trial of SY-1365 is a multi-center, open-label trial designed to evaluate the safety, tolerability and anti-tumor activity of SY-1365 in patients with advanced solid tumors. Following completion of the dose escalation portion of the trial, Syros opened expansion cohorts to further assess the potential of SY-1365 in multiple ovarian and breast cancer patient populations. The expansion cohorts are evaluating SY-1365: as a single agent in primary platinum-refractory ovarian cancer patients; as a single agent in ovarian cancer patients who have relapsed after three or more therapies; in combination with carboplatin in ovarian cancer patients who have relapsed after one or more prior therapies; and in combination with fulvestrant in patients with HR+ metastatic breast cancer who have progressed after treatment with a CDK4/6 inhibitor. An additional cohort is enrolling patients with any solid tumor accessible for biopsy to further evaluate the mechanism of action of SY-1365. Additional details about the trial can be found using the identified NCT03134638 at www.clinicaltrials.gov.