On March 31, 2019 Cyteir Therapeutics, a leader in the discovery and development of novel therapeutics based on the biology of DNA repair and synthetic lethality for the treatment of cancer and autoimmune diseases, reported the presentation of promising new preclinical data for the company’s lead compound, CYT-0851. The data are being shared this week at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting and suggest that the novel RAD51 inhibitor could be active as a monotherapy against B-cell lymphomas and multiple solid tumors, including pancreatic cancer (Press release, Cyteir Therapeutics, MAR 31, 2019, View Source [SID1234534791]). Data also show that CYT-0851 is potentially synergistic in combination with PARP inhibitors and may overcome PARP inhibitor resistance. Cyteir expects to initiate clinical trials with CYT-0851 in mid-2019.
Cyteir’s platform is based on the groundbreaking discovery of a relationship between activation-induced cytidine deaminase (AID), a DNA-damaging enzyme, and RAD51, a protein that is essential to the repair of DNA breaks. AID overexpression causes elevated DNA damage in high numbers of patients with B-cell malignancies and many patients with solid tumors. Cyteir is developing selective small-molecule compounds that the company believes inhibit RAD51. In preclinical models, reducing the ability of diseased cells to self-repair in this way causes them to become overwhelmed by their own DNA damage and undergo cell death – resulting in the therapeutic effect known as "synthetic lethality." Kevin Mills, Ph.D., Cyteir’s co-founder and chief scientific officer, led the research that first identified the synthetic lethality relationship between RAD51 and AID.
"The data being presented at this year’s AACR (Free AACR Whitepaper) meeting validate the mechanism-of-action underlying our novel synthetic-lethality approach and confirm that we have identified a potent, selective oral inhibitor that has the potential to broadly target multiple cancers with high levels of DNA damage induced by AID," said Markus Renschler, M.D., Cyteir president and CEO. "We are on track to file an IND mid-year and look forward to seeing how this exciting new mechanism performs in clinical trials as we look to improve outcomes for patients with advanced cancers."
Three presentations at AACR (Free AACR Whitepaper) 2019 support the potential of CYT-0851 to provide an effective, targeted new treatment option for a variety of hematologic cancers and solid tumors. Data presented by the company today demonstrate in vitro that CYT-0851 is synergistic and may be active as a combination therapy with PARP inhibitors (Poster Section 14, Board 363/24). Researchers tested five PARP inhibitors, each in combination with CYT-0851 in multiple tumor-derived cell lines with varying levels of AID expression and PARP inhibitor sensitivity. Findings suggest that CYT-0851 enhances the synthetic lethal activity of PARP inhibitors and may re-sensitize tumors that are resistant to this class of therapy.
Data scheduled for presentation tomorrow validate – in preclinical models – the mechanism-of-action of CYT-0851 in AID overexpressing cancers, demonstrating that the compound reduces activity of RAD51, reduces levels of DNA repair, and increases levels of DNA damage leading to the death of cancer cells (Poster Section 35, Board 2566/10).
On Wednesday, Cyteir will present data from a preclinical study evaluating the in vivo activity of CYT-0851 in AID-overexpressing B-cell lymphomas and solid tumors, particularly pancreatic cancer (Poster Section 10, Board 4730/20). In this study, oral administration of the compound in three patient-derived pancreatic cancer xenograft models led to significant anti-tumor activity.