Green3Bio announces the publication of preclinical data demonstrating that inhibition of SIK2 (including GRN-300) synergistically enhances the activity of PARP inhibitors in ovarian and triple-negative breast cancers.
Frisco, Texas, June 24, 2022 /PRNewswire/ — Green3Bio, a subsidiary of Greenfire Bio, today announced publication in the Journal of Clinical Investigation1 led by researchers from The University of Texas MD Anderson Cancer Center demonstrating that SIK2 inhibitors including GRN-300 sensitized triple negative ovarian and breast cancer (TNBC) cells and xenografts to PARP inhibitors.
Zhen Ludoctor and Robert BastMD and colleagues demonstrated that a combination of PARPi and SIKi provides a novel therapeutic approach to improve PARPi sensitivity in ovarian cancers that initially respond to PARPi and eventually develop drug resistance.
Key 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
- Transcription of DNA repair and apoptosis genes is regulated by inhibition of SIK2 by GRN-300
- GRN-300 improves 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 results 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, have shown no significant toxicity based on weight loss. Preclinical toxicology studies in rodents and dogs showed no hematological toxicity, which is particularly important for the association with PARPi.
“Patients with ovarian and triple-negative breast cancers are in dire need of more effective treatments due to the high prevalence of acquired resistance to standard therapies that involve PARP inhibition,” said Steve Morris, MD (Chair of the Greenfire Bio Scientific Advisory Board). He added: “Preclinical data of GRN-300 published in The Journal of Clinical Investigation shows the potential of GRN-300 and its unique mechanism of action through inhibition of SIK2/3 to help change the paradigm of combination therapy. in gynecological and breast cancers, regardless of BRCA mutation status.”
Ajit GillCEO and Founder of Greenfire Bio, said: “This publication provides further support for the development of our clinical asset GRN-300. We believe this agent has the potential to improve the treatment of ovarian cancers and other cancers – both as a single agent and in combination with existing therapies such as the inhibitor olaparib of PARP, which is indicated for the treatment of ovarian and breast cancers under the trade name Lynparza. »
These data further support the preclinical proof of concept of SIK2 inhibitors as potential cancer therapies in combination with carboplatin for difficult-to-treat ovarian cancer, recently published in Cancerand they support the ongoing efforts of our ongoing first-in-man clinical trial at MD Anderson.
About ovarian cancer
According to American Cancer Society2, ovarian cancer is the fifth most common cancer death among women. They estimate that in 2022 there will be approximately 19,880 new cases of ovarian cancer diagnosed in United States and that approximately 12,810 will die from the disease. According to World Cancer Research Fund International3, there were approximately 313,000 new cases of ovarian cancer diagnosed worldwide in 2020. Ovarian cancer is difficult to detect at an early stage and more treatable; therefore, the current lack of salvage therapy for women who experience a recurrence results in a 5-year survival rate of less than 30%.
GRN-300 (formerly ARN3261) is a novel, first-in-class, orally bioavailable, small-molecule dual inhibitor of salt-inducible kinases 2 and 3 (SIK2, SIK3). This agent has the potential to overcome chemoresistance due to its mechanism of action (MOA) and synergistic effects with standard of care including paclitaxel, carboplatin, PARP inhibitors and immune checkpoint inhibitors (HERE). SIK2 is overexpressed in 30% of ovarian cancer samples, 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 SIK2 expression were found to be significantly correlated with poor progression-free survival in patients with high-grade serous ovarian cancers. GRN-300 attenuated tumor growth and inhibition in several preclinical xenograft models of ovarian cancer as a single agent and in combination with paclitaxel. The clinical activity of GRN-300 as monotherapy and in combination with paclitaxel is currently being evaluated in phase 1a/1b Clinical study in subjects with recurrent cancers of the ovary, primary peritoneum and fallopian tubes (ClinicalTrials.gov ID: NCT04711161).
About Greenfire Bio
Greenfire Bio, led by a team of experienced biopharmaceutical executives, is building a diverse portfolio of oncology products through licensing, acquisitions and partnerships, and advancing them through clinical proof of concept.
Green3Bio is a subsidiary of Greenfire Bio. Green3Bio is developing GRN300 through clinical trials with the expertise of Greenfire Bio team members. The currently ongoing clinical trial (ClinicalTrials.gov Identifier: NCT04711161) is sponsored by Green3Bio.
1 J Clin Invest. 2022;132(11):e146471
Ajit GillPresident and CEO of Greenfire Bio in [email protected].
Website: greenfirebio.com LinkedIn: https://www.linkedin.com/company/greenfire-bio/
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