P2, N=63, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial primary completion date: Sep 2025 --> Jun 2026

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.

The combination of RT + ATRi resulted in increased T cell activation compared to the combined treatment with ATMi, respectively. This suggests an advantage of ATRi in comparison to ATMi in combination with RT for induction of beneficial anti-tumor immune responses in HNSCC.

P2/3, N=120, Active, not recruiting, Global Coalition For Adaptive Research Inc. | Recruiting --> Active, not recruiting

P1, N=94, Recruiting, Mayo Clinic | Trial completion date: Feb 2029 --> May 2029 | Trial primary completion date: Feb 2028 --> May 2028

To overcome these hurdles, we developed a bone-targeted, glutathione (GSH)-responsive polymeric nanoparticle (NPALN/Mn-AP) that chelates manganese (Mn) and delivers an ATM inhibitor (AZD0156) and a PRMT5 inhibitor (GSK3326595). By functionalizing this nanoplatform with alendronate (ALN) into NPALN/Mn-AP, we achieve preferential accumulation in bone tumors...In vivo studies demonstrate that NPALN/Mn-AP significantly inhibits OS progression and boosts systemic immune responses. This dual-action, bone-specific nanotherapeutic platform synchronized DNA-repair inhibition and Mn-enhanced immune-stimulation, offering a promising new approach for effective osteosarcoma treatment.

Given the critical role of the serine/threonine kinase ataxia telangiectasia mutated (ATM) in detecting DNA double-strand breaks and coordinating HR repair, we investigated whether ATM contributes to IFN-γ resistance by using the ATM inhibitor KU-55933...Mechanistically, the combination of IFN-γ treatment and ATM inhibition elicited a robust DNA damage response and disrupted glutathione metabolism, reducing the GSH/GSSG ratio and thereby promoting ferroptosis through increased susceptibility to oxidative stress. These findings highlight the pivotal role of DNA damage response pathways in mediating the anti-tumor effects of IFN-γ.

P1, N=54, Recruiting, Children's Oncology Group | Initiation date: Feb 2026 --> Jun 2025

The observed genotype-specific or drug-induced increase in radiosensitivity towards proton beam radiotherapy highlights the promise of genetic profiling of DSB repair defects for biology-driven patient stratification and the use of PARP-inhibitors in guiding personalized proton radiotherapy strategies.

P2, N=63, Active, not recruiting, EMD Serono Research & Development Institute, Inc. | Trial completion date: Jan 2028 --> Jun 2026 | Trial primary completion date: Jan 2028 --> Sep 2025

In xenograft models, AZD0156 combined with cisplatin substantially suppressed tumor growth compared to monotherapy, with acceptable tolerability profiles. These findings identify ATM inhibition as a promising strategy to overcome gemcitabine resistance in CCA, particularly in tumors with compromised alt-NHEJ repair capacity, providing a mechanistic rationale for clinical development of this combination therapy.

Finally, the combination of radiotherapy and ACPP-AZD0156 potentiated immune checkpoint inhibitors that resulted in durable tumor control. The therapeutic synergies of ACPP targeted ATM inhibitor to radiosensitize and stimulate anti-tumor immune responses provides a rationale for developing tumor-targeted radiosensitizer drug conjugates that restrict radiosensitization to cancer cells that then engages anti-tumor immune responses to improve cancer patient outcomes.