On October 30, 2017 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 data supporting the ongoing clinical development strategy for its Chk1 inhibitor, SRA737 (Press release, Sierra Oncology, OCT 30, 2017, View Source [SID1234521304]). The results were presented in a poster on October 29th at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) held in Philadelphia, Pennsylvania.
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“The data generated from these experiments are consistent with recent findings from our research and demonstrate that a potent and selective Chk1 inhibitor such as SRA737 can effectively synergize with sub-therapeutic doses of gemcitabine to induce replication catastrophe and tumor cell death,” said Dr. Alan R. Eastman, Professor at the Geisel School of Medicine at Dartmouth and the founding Director of the Molecular Therapeutics Research Program of the Norris Cotton Cancer Center at Dartmouth-Hitchcock. “I look forward to results from the clinical study Sierra is conducting which translates this novel strategy for the treatment of patients with advanced cancers.”
“Chk1 is essential for managing replication stress (RS), which is intrinsically elevated in certain oncogene-transformed tumors, and can also be further enhanced by chemotherapeutic drugs like gemcitabine. While gemcitabine likely causes RS by depleting deoxynucleotide (dNTP) and damaging DNA, Chk1 protects against RS through a variety of molecular mechanisms. Consequently, tumor cells become highly reliant on Chk1 to manage replication stress and its downstream consequences in order to survive and continue to proliferate,” added Dr. Christian Hassig, Senior Vice President of Research at Sierra Oncology. “Through our research, we have demonstrated that SRA737 has the potential to synergize with several clinically important chemotherapeutic inducers of RS to kill tumor cells in vitro at low concentrations. We also demonstrated that the combination of SRA737 and gemcitabine may prove efficacious in gemcitabine-resistant clinical settings and that SRA737 can be potentiated by sub-therapeutic doses of gemcitabine in animal models of cancer.”
“Replication stress has been recognized as a potent driver of genomic instability, a fundamental hallmark of cancer, and is rapidly emerging as an area of dynamic scientific research,” stated Dr. Nick Glover, President and CEO of Sierra Oncology. “Tumors harboring high levels of intrinsic or exogenous forms of replication stress are potential candidates for therapeutic intervention using SRA737. We are actively leveraging these concepts in our ongoing monotherapy and low-dose gemcitabine combination clinical trials.”
About the Poster
Title: The Chk1 inhibitor, SRA737, demonstrates chemical synthetic lethality with replication stress-inducing agents, including novel low-dose gemcitabine, in preclinical models of cancer.
Poster #181; Abstract #B181:
The Poster is available on the company’s website at www.sierraoncology.com.
Data reported in the Poster demonstrated that:
The combination of SRA737 with a range of RS-inducing agents was highly synergistic in a panel of 15 cell lines of diverse tissue lineages, with the strongest synergy observed with gemcitabine.
Profound synergy between SRA737 and gemcitabine was observed in several bladder cancer cell lines as well as in human patient-derived bladder cancer 3D cultures, further supporting the clinical development of this RS-inducing combination.
Significant anti-tumor activity and increased survival (vs. control) were observed when SRA737 and gemcitabine were dosed in combination in a highly aggressive gemcitabine resistant bladder carcinoma PDX model. These findings suggest that the combination of SRA737 and gemcitabine may be efficacious in gemcitabine-resistant clinical settings.
Strikingly, anti-tumor activity was observed when SRA737 was combined with a sub-therapeutic dose of gemcitabine in xenograft models of colorectal adenocarcinoma and osteosarcoma. This combination was shown to increase RS markers by three to five-fold over the change noted with gemcitabine alone. These findings support i) the development of SRA737 in combination with low, sub-therapeutic doses of gemcitabine and, ii) the broader application of this unique combination in tumor indications where gemcitabine is not standard of care.