- SRA737 demonstrates preclinical efficacy in aggressive CCNE1-amplified and MYCN‑overexpressing high-grade serous ovarian cancer patient-derived xenograft (PDX) models -
- PDX models were refractory to both platinum therapy and PARP inhibitors -
VANCOUVER, Nov. 15, 2018 /PRNewswire/ - Sierra Oncology, Inc. (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, today reported preclinical data for its novel oral Chk1 inhibitor, SRA737, in a poster presented at the 30th EORTC-NCI-AACR Symposium held in Dublin, Ireland.
"Oncogene-driven high-grade serous ovarian cancers (HGSOC) with CCNE1 (gene encoding cyclin E) and MYCN pathway activation exhibit defective cell cycle checkpoint control and replicative stress. The DNA damage response effector kinase, Chk1, modulates the cellular response to replicative stress and has been shown to be upregulated in these subtypes of HGSOC," said Dr. Clare Scott, Professor at The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. "Our pre-clinical results show that the Chk1 inhibitor SRA737 has impressive efficacy in our most aggressive models of ovarian cancer."
As detailed in the poster, the efficacy of single agent SRA737 was explored in two cyclin E overexpressing HGSOC patient-derived xenografts (PDX), and also compared to olaparib, a PARP inhibitor recently approved for HGSOC. Both PDX models had pronounced amplification of CCNE1; one also harbored a MYCN amplification. Both PDX models were insensitive to standard platinum-based therapy and did not harbor BRCA1/2 or related gene mutations. Treatment with SRA737 resulted in significant and differentiated anti-cancer activity, including dose dependent tumor regression. As anticipated, the PARP inhibitor olaparib was inactive.
"Sierra's ongoing SRA737-01 monotherapy and SRA737-02 low dose gemcitabine combination studies were recently prioritized for CCNE1-enriched HGSOC, a promising potential indication for Chk1 inhibition," stated Dr. Barbara Klencke, Chief Development Officer, Sierra Oncology. "We look forward to reporting clinical data from these studies in the first half of 2019."
The poster will be presented on Thursday, November 15th from 10:00 am – 5:30 pm (GMT).
Title: SRA737, a novel Chk1 inhibitor, shows efficacy in CCNE1-amplified and MYCN-overexpressing high-grade serous ovarian cancer patient-derived xenograft models
Authors: G.Y. Ho, H. Barker, C. Vanderberg, O. Kondrashova, E. Kyran, E. Lieschke, O. McNally, A. Hamilton, V. Heong, R. Hansen, S. Milutinovic, B. Strouse, M. Hedrick, C. Hassig, D. Bowtell, W. Matthew, C. Scott
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.
About Sierra Oncology
Sierra Oncology is a clinical stage drug development company advancing targeted therapeutics for the treatment of patients with unmet medical needs in hematology and oncology. Our lead drug candidate, momelotinib, is a potent, selective and orally-bioavailable JAK1, JAK2 and ACVR1 inhibitor that has been investigated in two completed Phase 3 trials for the treatment of myelofibrosis and has demonstrated a potentially differentiated therapeutic profile encompassing anemia-related benefits, as well as achieving substantive spleen and constitutional symptom control.
Sierra is also advancing SRA737 and SRA141. 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). 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. SRA141 is a Phase 1 ready, potent, selective, orally bioavailable small molecule inhibitor of Cell division cycle 7 kinase (Cdc7). Cdc7 is a key regulator of DNA replication and is involved in the DDR network, making it a compelling emerging target for the potential treatment of a broad range of tumor types.
For more information, please visit www.sierraoncology.com.
Cautionary Note on Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding Sierra Oncology's market and industry position, expectations from current data, anticipated clinical development activities and timing, expectations regarding when trial data may be reported, and potential benefits of Sierra Oncology's product candidates. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These statements are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements. Such forward-looking statements are subject to risks and uncertainties, including, among others, the risk that Sierra Oncology may be unable to successfully develop and commercialize product candidates, product candidates may not demonstrate safety and efficacy or otherwise produce positive results, Sierra Oncology may experience delays in the preclinical and anticipated clinical development of its product candidates, Sierra Oncology may be unable to acquire additional assets to build a pipeline of additional product candidates, Sierra Oncology's third-party manufacturers may cause its supply of materials to become limited or interrupted or fail to be of satisfactory quantity or quality, Sierra Oncology's cash resources may be insufficient to fund its current operating plans and it may be unable to raise additional capital when needed, Sierra Oncology may be unable to obtain and enforce intellectual property protection for its technologies and product candidates and the other factors described under the heading "Risk Factors" set forth in Sierra Oncology's filings with the Securities and Exchange Commission from time to time. Sierra Oncology undertakes no obligation to update the forward-looking statements contained herein or to reflect events or circumstances occurring after the date hereof, other than as may be required by applicable law.
View original content:http://www.prnewswire.com/news-releases/sierra-oncology-reports-preclinical-efficacy-for-chk1-inhibitor-sra737-in-treatment-refractory-ovarian-cancer-models-at-the-eortc-nci-aacr-symposium-300750660.html