On April 17, 2018 Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported preclinical results in two posters, including late-breaking data being presented today, for its Checkpoint kinase 1 (Chk1) inhibitor SRA737, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago, Illinois (Press release, Sierra Oncology, APR 17, 2018, View Source [SID1234525426]).
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"The data presented within these posters demonstrate that SRA737, as monotherapy and in combination with a poly ADP-ribose polymerase inhibitor (PARPi) such as niraparib, has anti-tumor activity across a broad range of settings. Anti-tumor activity was observed both in homologous recombination repair (HRR) proficient cancers which are poor candidates for PARPi alone, and in HRR deficient tumor cells that have acquired resistance to either PARPi and/or platinum agents," said Dr. Christian Hassig, Chief Scientific Officer of Sierra Oncology. "We also observed inhibition of tumor growth in aggressive CCNE1-driven high grade serous ovarian cancer (HGSOC) patient-derived xenografts. CCNE1 amplification is known to increase replication stress and genomic instability, leading to increased reliance on Chk1. Analogous to PARPi, which first exhibited robust activity in patients harboring BRCA mutations, Chk1 inhibitors such as SRA737 may prove effective in defined genetic backgrounds of high replication stress, such as CCNE1 amplification."
The efficacy of SRA737 monotherapy is currently being investigated in an ongoing Phase 1/2 clinical trial (NCT02797964) in replication stress-driven cancer including a patient cohort with CCNE1 amplified HGSOC.
Sierra is also planning to investigate SRA737 in combination with niraparib in a multicenter Phase 1b/2 study in subjects with metastatic castration-resistant prostate cancer (mCRPC), anticipated to be initiated in the fourth quarter of 2018. Janssen Research & Development, LLC will supply TESARO’s ZEJULA (niraparib) for the trial, which is to be led by Professor Johann de Bono, Regius Professor of Cancer Research, Head of the Division of Clinical Studies and Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.
The two posters will be available on the company’s website at www.sierraoncology.com.
SRA737 AACR (Free AACR Whitepaper) 2018 Late-Breaker: The Novel Oral Chk1 Inhibitor, SRA737, Is Active in Both PARP Inhibitor Resistant and CCNE1 Amplified High Grade Serous Ovarian Cancers
Data being presented in this late-breaking poster is from research conducted in the laboratory of Dr. Fiona Simpkins, Assistant Professor of Obstetrics and Gynecology at The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Approximately 20% of HGSOCs harbor CCNE1 gene amplification. CCNE1 amplification is known to increase replication stress and genomic instability, leading to increased reliance on Chk1. These tumors show intrinsic resistance to PARPi and frequently are, or become resistant to, platinum therapy, leaving patients without effective treatment options. In this research, Chk1 inhibition by SRA737 as monotherapy in CCNE1 amplified ovarian cancer models was shown to: a) increase levels of replication stress and DNA double strand breaks, b) in turn leading to excessive genomic instability, c) resulting in subsequent tumor cell death, tumor regression and a profound survival benefit.
A distinct subgroup comprising approximately 50% of HGSOC have defective HRR genes (e.g. BRCA1/2 mutation). HRR deficient HGSOC are initially sensitive to PARPi but drug resistance ultimately emerges, frequently involving genetic reversion of BRCA mutated genes and partial restoration of HRR. HRR deficiency may also elevate sensitivity to Chk1 inhibition, given the well-established role of Chk1 in HRR, as well as other aspects of the replication stress response. In this research, SRA737 demonstrated activity as a single agent, as well as in combination with PARPi, in acquired PARPi-resistant cells. Furthermore, SRA737 in combination with PARPi demonstrated preliminary evidence of synergistic tumor growth inhibition in a HGSOC patient-derived xenograft model.
SRA737 AACR (Free AACR Whitepaper) 2018 Poster: The Chk1 Inhibitor, SRA737, Synergizes with the PARP Inhibitor, Niraparib, to Kill Carcinoma Cells via Multiple Cell Death Pathways
Sierra presented a second poster at AACR (Free AACR Whitepaper) with data from research conducted in the laboratory of Dr. Paul Dent, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia. The results demonstrate that the combination of SRA737 and niraparib was effective in HRR proficient ovarian and breast tumor cell lines and that both autophagic cell death and apoptotic pathways contribute to SRA737/niraparib-induced tumor cell killing. PARPi monotherapy is known to be substantially less effective in treating patients with HRR proficient tumors, making the combination with SRA737 a novel and potentially more effective treatment option. Moreover, the involvement of multiple cell death mechanisms may decrease the potential for tumors to develop resistance to these agents.