On November 29, 2018 Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing targeted therapeutics for the treatment of patients with significant unmet needs in hematology and oncology, reported preclinical data for its novel oral Chk1 inhibitor, SRA737, in a poster presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Conference on Tumor Immunology and Immunotherapy in Miami Beach, Florida (Press release, Sierra Oncology, NOV 29, 2018, View Source [SID1234531745]).
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"In this study we found that the potent, selective oral Chk1 inhibitor, SRA737, activated the innate immune signaling STING pathway and demonstrated significant anti-tumor activity in an immunocompetent preclinical model of small cell lung cancer (SCLC)," said Dr. Lauren Byers, Associate Professor at the University of Texas MD Anderson Cancer Center, Houston, Texas. "Remarkably, the combination of SRA737 with an anti-PD-L1 immune checkpoint inhibitor induced tumor regression in this model, providing strong rationale for combining these agents to treat this immunotherapy refractory indication."
"SCLC remains a significant unmet need and one where immunotherapies have yielded limited efficacy. These tumors frequently harbor defects in cell cycle checkpoint and DNA damage repair (DDR) genes, with a coincident dependence on regulators of replication stress such as Checkpoint Kinase 1 (Chk1) as a compensatory mechanism," said Dr. Christian Hassig, Chief Scientific Officer, Sierra Oncology. "These encouraging preclinical results highlight an additional potential application for SRA737 that warrants further evaluation beyond our current clinical development programs for the drug as a monotherapy and in combination with replication stress-inducing low dose gemcitabine."
The poster will be presented on Thursday, November 29th from 5:00 to 7:00 pm (ET).
Title: The oral Chk1 inhibitor, SRA737, synergizes with immune checkpoint blockade in small cell lung cancer (SCLC).
Authors: Triparna Sen, Snezana Milutinovic, Robert J. Cardnell, Lixia Diao, Youhong Fan, Ryan J. Hansen, Bryan Strouse, Michael Hedrick, Christian Hassig, Jing Wang, Lauren A. Byers.
Location: Poster Session: B; Board Number: B15; Session Location: Americana 3 and 4
STING: Stimulator of Interferon Genes
About SRA737
SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key regulator of cell cycle progression and the DNA Damage Response (DDR). In cancer cells, intrinsic replication stress is induced by factors such as oncogenes (e.g., CCNE1 or MYC), genetic mutations in DNA repair machinery (e.g., BRCA1 or FANCA), genetic mutations leading to a dysregulated cell cycle (e.g., TP53 or RAD50) or other genomic alterations. This replication stress results in persistent DNA damage and genomic instability leading to an increased dependency on Chk1 for survival. Targeted inhibition of Chk1 by SRA737 may therefore be synthetically lethal to cancer cells with elevated intrinsic replication stress and have utility as a monotherapy in a range of tumor indications. The combination of SRA737 with other modalities, such as other agents that target the DDR network and certain chemotherapeutics, may also provide synergistic anti-tumor activity via a variety of potential biological mechanisms. Importantly, the oral bioavailability of SRA737 may afford greater dosing flexibility for both monotherapy and combination therapy settings than is possible with intravenously administered agents.
SRA737 is currently being investigated in two Phase 1/2 clinical trials primarily focused on patients with ovarian cancer: SRA737-01, a monotherapy study, and SRA737-02, a drug combination study evaluating SRA737 potentiated by low dose gemcitabine. Sierra has also prepared for a potential clinical study of SRA737 in combination with a PARP inhibitor.