On June 24, 2022 Green3Bio, a subsidiary of Greenfire Bio, reported a publication in the Journal of Clinical Investigation1 led by researchers at The University of Texas MD Anderson Cancer Center demonstrating that SIK2 inhibitors, including GRN-300 sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors (Press release, Greenfire, JUN 24, 2022, View Source [SID1234616243]).
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Zhen Lu, M.D., and Robert Bast, M.D., and colleagues demonstrated that a combination of PARPi and SIKi provides a novel therapeutic approach to enhance PARPi sensitivity in ovarian cancers that initially respond to PARPi and eventually develop drug resistance.
The major findings from the preclinical research study include:
GRN-300 treatment sensitizes ovarian and breast cancer cells by enhancing olaparib-mediated inhibition of PARP enzyme activity
The transcription of DNA repair and apoptosis genes is regulated by SIK2 inhibition by GRN-300
GRN-300 enhances olaparib-induced DNA DSB (double-strand break) and apoptosis
Co-administration of GRN-300 and olaparib is synergistic in inhibiting tumor growth in animal models of ovarian cancer and TNBC.
These findings provide strong preclinical evidence supporting future clinical trials to determine whether the combination will benefit patients with ovarian and triple negative breast cancers. Animal studies, particularly those with olaparib and GRN-300, did not show significant toxicity based on weight loss. Pre-clinical toxicology studies in rodents and dogs showed no hematologic toxicity, which is particularly important for combination with PARPi.
"Patients with ovarian and triple-negative breast cancers are in great need for more effective treatments due to the high prevalence of acquired resistance to standard therapies that involve PARP inhibition," said Steve Morris, MD (Chairperson, Scientific Advisory Board of Greenfire Bio). He added, "The GRN-300 preclinical data published in The Journal of Clinical Investigation shows the potential of GRN-300 and its unique mechanism of action through SIK2/3 inhibition to help change the combination treatment paradigm in gynecologic and breast cancers, irrespective of BRCA mutation status."
Ajit Gill, CEO and founder of Greenfire Bio, commented that "This publication provides further support for the development of our clinical asset GRN-300. We believe this agent has the potential to improve treatment of ovarian and other cancers – both as a single agent and in combination with existing therapies such as the PARP inhibitor olaparib that is indicated for the treatment of ovarian and breast cancers under the tradename Lynparza."
These data further support the preclinical proof-of-concept for SIK2 inhibitors as potential cancer therapeutics in combination with carboplatin for hard-to-treat ovarian cancer, recently published in Cancers, and they support the continued efforts in our first-in-human clinical trial ongoing at MD Anderson.
About Ovarian Cancer
According to the American Cancer Society, ovarian cancer ranks fifth in cancer deaths among women. They estimate that in 2022 there will be about 19,880 new cases of ovarian cancer diagnosed in the United States and that about 12,810 will die of the disease. According to the World Cancer Research Fund International, there were about 313,000 new cases of ovarian cancer diagnosed worldwide in 2020. Ovarian cancer is difficult to detect at an early, more treatable stage; therefore, the current lack of salvage treatment for women, who experience a recurrence, results in a 5-year survival rate of less than 30%.
About GRN-300
GRN-300 (previously ARN3261) is an orally bioavailable first-in-class novel, small molecule, dual inhibitor of the salt-inducible kinases 2 and 3 (SIK2, SIK3). This agent has the potential to overcome chemoresistance based on its mechanism of action (MOA) and synergistic effects with standard of care including paclitaxel, carboplatin, PARP inhibitors, and immune checkpoint inhibitors (ICIs). SIK2 is overexpressed in 30% of ovarian cancer specimens suggesting a multifunctional role of SIK2/3 in tumorigenesis. SIK2 and SIK3 are known to play [an] oncogenic role in other tumor types, including prostate cancer, breast cancer, diffuse large B-cell lymphoma, and melanoma. Higher levels of expression of SIK2 have been shown to be significantly correlated with poor progression-free survival in patients with high-grade serous ovarian cancers. GRN-300 attenuated tumor growth & inhibition in several preclinical xenograft ovarian cancer models as a single agent and in combination with paclitaxel. The clinical activity of GRN-300 as a single agent and in combination with paclitaxel is currently being evaluated in a Phase 1a/1b Clinical Study in subjects with Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers (ClinicalTrials.gov Identifier: NCT04711161).