peposertib (M3814)

Scramble LNCaP, BRCA1 KO, and BRCA2 KO cells were treated with the PARPi talazoparib, the DNA-PK inhibitor nedisertib and their combination. Therapeutically targeting NHEJ presents a promising approach in treating BRCA-mutated PCa. Further in vivo investigations are required to assess the tolerability of this drug combination.

P1, N=29, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2025 --> Dec 2027 | Trial primary completion date: Oct 2025 --> Dec 2027

P1, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2025 --> Dec 2025 | Trial primary completion date: Sep 2025 --> Dec 2025

Inhibition of the Artemis activator, DNA-PKcs, with peposertib (M3814) sensitizes B cells to Top2 poisons while ATM or ATR inhibition does not...Clinical data demonstrates that high Artemis expression correlates with poor survival in several cancers, and we demonstrate that Artemis function is critical for survival following combination drug treatment. These insights can be leveraged to unlock new avenues for the treatment of aggressive cancers by enhancing the cytotoxicity of agents through blockade of DNA break repair.

Both genetic and pharmacological perturbation of DNA-PK enhance radiosensitivity in TP53-deficient SHH medulloblastoma, leading to cell death. In vivo treatment of both somatic and germline TP53-mutant SHH medulloblastoma models with peposertib, a small-molecule inhibitor of DNA-PK, significantly improves survival when combined with radiotherapy, strongly supporting further clinical investigation.

P1, N=48, Suspended, National Cancer Institute (NCI) | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2025 --> Jun 2026

We further compared the inhibitory effects of olaparib and peposertib, specific inhibitors of single-strand break (SSB) and DSB repair, respectively. Peposertib, a DNA-PKcs inhibitor, significantly reduced ITD formation, highlighting the role of non-homologous end joining. Our findings suggest a potential therapeutic approach to prevent de novo FLT3-ITDs in AML.

P1, N=27, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2025 --> Mar 2026 | Trial primary completion date: Mar 2025 --> May 2024

177Lu-DOTA-girentuximab (targeting carbonic anhydrase IX) or 177Lu-DOTA-rosopatamab (targeting prostate-specific membrane antigen) was used to deliver β-radiation to tumors via a single intravenous dose (3 or 6 MBq) in mice bearing SK-RC-52 RCC or LNCaP prostate cancer xenografts, respectively. Our findings suggest a synergistic effect between peposertib and 177Lu-based radioimmunotherapy, wherein peposertib enhanced the efficacy of radioimmunotherapy. This synergy indicates the potential to reduce the necessary dose of radioimmunotherapy for effective cancer treatment.

P1/2, N=455, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Trial completion date: Aug 2027 --> Feb 2031 | Trial primary completion date: Aug 2027 --> Feb 2031

P1, N=42, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

This is also recapitulated in-vivo, where HPV+ UD-SCC-2 xenografts display stronger and more durable responses to the combined treatment as compared to p53 wild-type UM-SCC-74A tumors. In conclusion, DNA-PKcs inhibitor peposertib should be further studied as a potential radiosensitizer for HNSCCs, taking into consideration the genetic background and the HPV status of a particular tumor.