On April 3, 2017 Sierra Oncology, Inc. (NASDAQ: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response therapeutics for the treatment of patients with cancer, reported that preclinical results for its Chk1 inhibitor, SRA737, were presented on April 2 in a poster at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held in Washington D.C (Press release, Sierra Oncology, APR 3, 2017, View Source [SID1234518421]). This research was conducted in the laboratory of Professor Paul Workman, Chief Executive and President of The Institute of Cancer Research (ICR), London, UK, and funded by Wellcome. Schedule your 30 min Free 1stOncology Demo! "These data demonstrate that inhibition of B-family DNA polymerases, POLA1, POLE and POLE2, combined with inhibition of Chk1, is synthetically lethal in numerous cancer cell lines," noted Professor Workman. "This supports the genetically-driven clinical development strategy Sierra intends to pursue for SRA737. For example, subsets of colon and endometrial cancers with POLE mutations may be sensitive to CHK1 inhibitors as monotherapy. In addition, gemcitabine is known to impair the B-family DNA polymerases, further supporting the rationale for its clinical combination with SRA737."
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"The ICR is a world-class cancer research institution and we are fortunate to maintain an ongoing collaborative relationship for the development of SRA737. In particular, the data reported by Professor Workman’s laboratory continues to reinforce the synthetic lethality hypothesis for SRA737, and further validates our approach to developing our lead drug," said Dr. Nick Glover, President and CEO of Sierra Oncology. "Appropriate patient selection is critical for clinical success. Fortunately, the biology underlying Chk1’s role in cancer and the DNA Damage Response suggest numerous opportunities where a patient’s specific tumor genetics might be linked to their predicted response to SRA737."
The poster, entitled: "Screening the druggable genome for synthetic lethal interactions with the CHK1 inhibitor PNT737" is available at www.sierraoncology.com. Additional information including full abstracts can be found at www.aacr.org.
About SRA737
SRA737, is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), currently being evaluated in two Phase 1 clinical trials in patients with advanced cancer.
The first trial is evaluating SRA737’s potential to induce synthetic lethality as monotherapy. Sierra recently proposed amendments to this trial to prospectively enroll subjects with tumors identified to have genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition. The study will employ a genetic selection algorithm targeting mutations in TP53, BRCA1, BRCA2, MYC, RAS, or other related genes associated with tumor suppression, oncogenesis, DNA damage repair, and replicative stress. Additionally, Sierra intends to modify the study to assess SRA737’s clinical activity across several cancer indications that harbor these genetic mutations including, for example, cohorts of subjects with 1) previously treated metastatic colorectal cancer; 2) platinum-resistant ovarian cancer; 3) metastatic castration-resistant prostate cancer; 4) advanced non-small cell lung cancer; and 5) advanced head and neck squamous cell carcinoma.
Sierra is currently also evaluating SRA737 in combination with gemcitabine and gemcitabine plus cisplatin. The company intends to modify the design of this clinical trial to expand enrollment in the gemcitabine combination following the completion of dose escalation. Subjects with 1) advanced bladder cancer and 2) advanced pancreatic cancer will be enrolled into genetically-selected dose expansion cohorts, employing a genetic selection algorithm similar to that to be used in the monotherapy protocol.