The findings support the initiation of a Phase 1 trial testing the compound early next year, investigators said.
Researchers from Syros presented the findings in a poster titled “Preclinical evaluation of PK, PD, and anti-tumor activity of the oral, non-covalent, potent and highly selective CDK7 inhibitor, SY-5609, provides rationale for clinical development in multiple solid tumor indications.” The poster was presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 26-30 in Boston.
SY-5609 is a small molecule that serves as an oral inhibitor of cyclin-dependent kinase (CDK) 7. CDKs regulate transcription, which is the process by which DNA is transformed into RNA, leading to gene expression. Therefore, they are potential therapeutic targets for cancers that have to activate or silence specific gene pathways to survive.
The preclinical experiments evaluated the effect of different doses of SY-5609, given daily to immunosuppressed mice implanted with cancer tissue extracted from patients — a research model called xenograft.
Results showed that SY-5609 inhibited tumor growth in a dose-dependent manner. The study also found that a significant reduction in tumor size was achieved at doses as low as one-fifth of the maximum tolerated dose in xenografts of ovarian and breast cancer.
The therapy was tested on 12 models of difficult-to-treat solid tumors, including triple-negative breast cancer, small lung cell carcinoma, and high-grade serous ovarian cancer. All of the models responded to the treatment. Additionally, 58% of the models showed a sustained response after the end of the treatment.
The researchers also observed that the inhibition of tumor growth was related to changes in gene expression caused by CDK7 inhibition. Models with altered expression of the RB pathway — a pathway that gets inactivated in a significant number of cancers — responded better and for longer to SY-5609 treatment.
“We are excited to share these new preclinical data for SY-5609, which speak to its potential as a best-in-class oral CDK7 inhibitor and reinforce our conviction in CDK7 inhibition as a potentially transformative approach for difficult-to-treat cancers,” Eric R. Olson, PhD, Syros’ chief scientific officer, said in a press release.
“We are particularly encouraged that SY-5609 as a single agent induced rapid and dose-dependent tumor growth inhibition in preclinical models of lung, breast and ovarian cancers, and by the observation that sustained regressions are associated with RB pathway alterations. These data support the focus of our planned Phase 1 trial on those patient populations, which we believe are most likely to benefit from treatment with SY-5609, and we look forward to initiating the study early next year.”
Syros expects to complete the experiments to support a new drug application by the end of the year. The company plans to initiate a Phase 1 trial in patients with different types of solid tumors with alterations in the RB pathway, including ovarian cancer, in the first quarter of 2020.
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