We demonstrate that inhibitors against ATR (AZD6738), and particularly ATM (AZD1390) and DNA-Pkcs (AZD7648), could significantly decrease clonogenic survival of HNSCC cell lines following PBT at both low and relatively high LET (~2 keV/µm and ~8 keV/µm, respectively). We confirmed that the inhibitors in combination with PBT led to DSB persistence through neutral comet assays and monitoring γH2AX/53BP1 foci. We also show that this strategy can enhance the sensitivity of patient-derived organoids of HNSCC to PBT of both low and high LET, highlighting this as a strategy which should be exploited further.

P1, N=30, Recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> Nov 2026 | Trial primary completion date: May 2026 --> Nov 2026

P1, N=570, Recruiting, Sanofi | Not yet recruiting --> Recruiting

In vitro, ESCC cell lines (TE13 and Eca9706) were co-treated with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitors (AZD7648 or NU7741) or PRKDC-targeting siRNA plus irradiation...Our study reveals a novel mechanism by which DNA-PKcs inhibition augments radiosensitivity in ESCC. Targeting DNA-PKcs could represent a promising strategy to improve the efficacy of radiotherapy in ESCC, offering a potential therapeutic approach to overcome radioresistance.

P1/2, N=90, Recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Apr 2026 --> Apr 2027

Collectively, our findings highlight the therapeutic potential of KU-57788 in ATC while revealing an intrinsic resistance mechanism mediated by DRP1 activation and the potential involvement of the NRF2/SLC7A11/GSH axis. More importantly, we provide strong evidence that combining KU-57788 with ferroptosis inducers significantly enhances its anticancer efficacy, offering a promising therapeutic strategy for ATC.

This study highlights the prognostic relevance of MRGs in BLCA. The nine-gene signature may serve as a useful framework for risk stratification in BLCA, while the identified risk genes and candidate compounds provide a basis for further biological and experimental investigation rather than direct therapeutic inference.

P1, N=570, Not yet recruiting, Sanofi

P1/2, N=123, Recruiting, Novartis Pharmaceuticals | N=73 --> 123

Three genes (MXRA7, PLEKHG4B and ATP2B4) were identified to construct a SERG-related model in BLCA, which provides a basis for understanding BLCA pathogenesis and new insights into BLCA treatment.

P1/2, N=61, Not yet recruiting, Novartis Pharma AG

P1/2, N=103, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting