On April 16, 2018 Syros Pharmaceuticals (NASDAQ: SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of genes, reported new preclinical data showing that SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor currently in a Phase 1 trial in patients with advanced solid tumors, demonstrated potent anti-tumor activity in multiple models of heavily pretreated ovarian cancer (Press release, Syros Pharmaceuticals, APR 16, 2018, View Source [SID1234525362]). These data were presented by Syros and its collaborators from the Dana-Farber Cancer Institute (DCFI) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago.
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"Despite recent advances in treating ovarian cancer, many patients either don’t respond or become resistant to treatment, and the outlook for these patients is poor," said Panagiotis A. Konstantinopoulos, M.D, Ph.D., Director of Translational Research and attending oncologist in the Gynecologic Oncology Program at DCFI and an Associate Professor of Medicine at Harvard Medical School. "SY-1365 stopped tumor growth in multiple preclinical models of ovarian cancer that had progressed following treatment with standard-of-care and targeted therapies. These data suggest SY-1365 has the potential to be an important new therapy for ovarian cancer that warrants further clinical investigation."
Researchers from Syros and DCFI evaluated the anti-tumor activity of SY-1365 in a broad panel of ovarian cancer cell lines, as well as in patient-derived xenograft (PDX) mouse models developed from patients treated with multiple prior therapies, including standard-of-care platinum-based therapies and a new class of targeted therapies known as PARP inhibitors. The data, which were presented in a poster discussion session and a poster session, show that SY-1365:
Induced cell death in numerous ovarian cancer cell lines.
Inhibited tumor growth in 10 of the 17 treatment-relapsed ovarian PDX models studied, including inducing complete regressions. Notably, these responses were observed irrespective of BRCA status or sensitivity to a PARP inhibitor.
Lowered expression of MCL1, a gene in the mitochondrial apoptosis pathway that is known to inhibit apoptosis, or programmed cell death.
The data also showed that sensitivity to SY-1365 was associated with low expression of BCLXL, a known apoptosis inhibitor, and RB1, a known tumor suppressor, pointing to potential biomarkers that may be predictive of response to SY-1365.
"We are very encouraged by these data," said David A. Roth, M.D., Chief Medical Officer of Syros. "CDK7 has emerged as a potentially important new drug target in cancer. By selectively inhibiting CDK7, SY-1365 has been shown to lower the expression of cancer driving genes and hit cancer cells at multiple points in the cell cycle, preferentially killing cancer cells and inhibiting tumor growth in preclinical models of a number of difficult-to-treat solid tumors and blood cancers. These newest data in ovarian cancer provide strong support for the planned expansion of our Phase 1 clinical trial into ovarian cancer and further highlight the promise of SY-1365 to make a profound difference for patients."
The ongoing Phase 1 trial of SY-1365 is a multi-center, open-label trial enrolling patients with advanced solid tumors. The primary objective of the trial is to assess the safety and tolerability of escalating doses of SY-1365, with the goal of establishing a maximum tolerated dose and a recommended Phase 2 dose and regimen. The dose-escalation phase is open and expected to enroll approximately 35 solid tumor patients for whom standard curative or palliative measures do not exist or are no longer effective. Following the dose-escalation phase, Syros plans to open expansion cohorts to further evaluate the safety and anti-tumor activity of SY-1365 as a single agent and in combination with standard-of-care therapies in multiple ovarian and breast cancer populations.
Syros expects to open the expansion phase of the trial in mid-2018 and to report data from the dose escalation portion of the trial in the fourth quarter of 2018.
About SY-1365
SY-1365 is a first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor with potential across a range of difficult-to-treat solid tumors and blood cancers. In preclinical studies, SY-1365 has shown significant anti-proliferative and pro-apoptotic activity in difficult-to-treat cancers, including breast and ovarian cancers and acute leukemia. SY-1365 has also been shown to preferentially kill cancer cells over non-cancerous cells and lower the expression of cancer-driving genes, inducing significant anti-tumor activity, including complete tumor regressions, in preclinical models of these cancers. SY-1365 is currently in a Phase 1 clinical trial in patients with advanced solid tumors, with planned expansion cohorts to evaluate SY-1365 in multiple ovarian and breast cancer patient populations as a single agent and in combination with standard-of-care therapies. Additional details about the trial can be found using the identifier NCT03134638 at www.clinicaltrials.gov.