P1, N=30, Recruiting, The Netherlands Cancer Institute | N=15 --> 30 | Trial completion date: Mar 2024 --> Jul 2028 | Trial primary completion date: Mar 2024 --> Mar 2026

A Phase Ia clinical trial (NCT05002140) with XRD-0394 in combination with RT has completed. These results provide a rationale for future clinical trials with XRD-0394 in combination with RT, PARP inhibitors and targeted delivery of topoisomerase I inhibitors.

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Feb 2025 --> Apr 2026 | Trial primary completion date: Feb 2025 --> Apr 2026

P1, N=37, Recruiting, Nader Sanai | Trial primary completion date: Jan 2024 --> Jul 2024

We demonstrated the efficacy of the combination of ATM and EZH2 inhibition against BAP1-deficient mesothelioma in preclinical models, indicating the potential of this combination as a novel treatment modality using BAP1 as a biomarker.

Molecular docking and dynamic simulation analyses highlight strong binding affinities of quercetin for Y2080D and AZD0156 for C2770G, suggesting potential therapeutic options...The study underscores the significance of Y2080D and C2770G mutations, offering valuable insights for future precision medicine targeting-specific ATM. Despite informative computational analyses, a significant research gap exists, necessitating essential in vitro and in vivo studies to validate the predicted effects of ATM mutations on protein structure and function.

A radiosensitizing effect can be confirmed after treatment with AZD0156, Afatinib or Alpelisib in three organoid lines using this assay so far. Establishment of HNSCC organoids was successful using our workflow. These 3D models can be used to screen for potential radiosensitizers. For validation, we established an organoid formation assay to determine the clonogenic survival as an important endpoint in radiobiology.

KU-55933 was predicted as a putative therapeutic drug for BC targeting VAMP7. VAMP7 was upregulated in BC tissue and correlated with poor prognosis of BC patients. VAMP7 may promote BC progression by targeting the cell cycle pathway.

We evaluated the effects of AZD1390 or a structurally related compound AZD0156 on innate immune signaling and found that both inhibitors enhanced radiation-induced T1IFN expression via the POLIII/RIG-I/MAVS pathway. Adaptive immune responses to combination therapy provided systemic control of contralateral tumors outside of the radiation field. Taken together, we show that a clinical candidate ATM inhibitor enhances radiation-induced T1IFN leading to both innate and subsequent adaptive anti-tumoral immune responses and sensitization of otherwise resistant pancreatic cancer to immunotherapy.

Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53-mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53-mutant cells to ATM inhibitor-mediated radiosensitization.

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Dec 2026 --> Feb 2025 | Trial primary completion date: Dec 2026 --> Feb 2025

Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (K 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies.

Finally, we identified a negative correlation between changes in phospho-ATM and PD-L1 levels in TNBC post- and pre-neoadjuvant therapy. This study reveals a novel mechanism by which ATM negatively regulates PD-L1 by downregulating JNK/c-Jun/TNF-α in TNBC, shedding light on the wide application of immune checkpoint blockade therapy for treating multi-line-resistant TNBC.

NRIP3 was frequently methylated in both colorectal adenomatous polyps and CRC. The methylation of NRIP3 may potentially serve as an early detection, late-onset, and poor prognostic marker in CRC. NRIP3 is a potential tumor suppressor. NRIP3 methylation is a potential synthetic lethal marker for combined PI3K and ATR/ATM inhibitors.

P1, N=67, Recruiting, Mayo Clinic | Not yet recruiting --> Recruiting

P1, N=12, Completed, XRad Therapeutics Inc | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Jul 2023 | Trial primary completion date: Dec 2023 --> Jul 2023

The five AML cell lines demonstrated sensitivity to monotherapy with GSK-368, AZD-1390, or AZD-6738 (EC50 value ranges from 5.461 to 7.349 nM, 5.821 to 10.120 nM, and 7.618 to 10.100 nM, respectively). DNMT1, ATM, and ATR possess potential as therapeutic targets for AML. Both individual targeting and combination targeting of these molecules have been confirmed as promising therapeutic approaches for AML.

Further analysis revealed that KU-55933 potentiates Olaparib-induced cell apoptosis by inhibiting ATM phosphorylation. Our study demonstrates that inhibiting ATM could enhance the sensitivity of endometrial cancer to Olaparib, thereby providing a potential alternative treatment for the clinical treatment of endometrial cancer.

P1, N=67, Not yet recruiting, Mayo Clinic | Trial completion date: Oct 2028 --> Feb 2029 | Trial primary completion date: Oct 2027 --> Feb 2028

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

P1, N=15, Terminated, EMD Serono Research & Development Institute, Inc. | Completed --> Terminated; The study was terminated early per sponsor decision to halt further development of M3541 due to pharmaceutical and PK/pharmacodynamics properties that precluded further clinical development.

Importantly, STAG2 expression correlates with poor prognosis of cancer patients. STAG2 is identified as an important regulator of HR and a potential therapeutic strategy for STAG2-mutant tumors is elucidated.

Inhibition of ATM reduced both glycolytic enzymes and OXPHOS levels in oncogene-driven cancer cells and enhanced apoptosis induced by driver inhibitors thus highlighting the possibility to use ATM and the driver inhibitors in combined regimens of anticancer therapy in vivo.

Our results demonstrate that AZD1390 effectively sensitizes breast cancer CNS metastasis to radiation therapy in DDR mutant tumors. This study demonstrates the potential of using AZD1390 as a novel therapeutic agent for patients with breast cancer CNS metastasis.

P1, N=67, Not yet recruiting, Mayo Clinic | Trial primary completion date: Oct 2028 --> Oct 2027

Of them, two market drugs approved by the Food and Drug Administration (AT-13387 and KU-55933) have emerged as candidates for HCC study. This new signature panel may serve as a potential prognostic marker, engendering the possibility of novel personalized therapy with classification of HCC patients.

Combined radiation and AZD0156 increase STING-dependent antitumor response. Tumor-derived cell-autonomous IFN-β amplification drives both MHC-I and PD-L1 induction at the tumor cell surface, which is required by anti-PD-L1 therapy to promote antitumor immune response following RT and AZD0156 combination therapy.

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Sep 2024 --> Dec 2024 | Trial primary completion date: Sep 2024 --> Dec 2024

P1, N=30, Completed, EMD Serono Research & Development Institute, Inc. | Active, not recruiting --> Completed

P1, N=11, Active, not recruiting, XRad Therapeutics Inc | Recruiting --> Active, not recruiting | N=38 --> 11

Using reactive oxygen species-sensitive polymeric micelles coloaded with Olaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), and AZD0156, an inhibitor of ataxia telangiectasia mutated (ATM), the resultant nanoformulation (M-TK-OA) disrupted both homologous recombination and nonhomologous end joining signaling of the DDR response and impaired colony formation in pancreatic cancer cells after RE. The efficacy of combined IRE and M-TK-OA treatments was partially attributed to the activation of cyclic GMP-AMP synthase-stimulator of interferon genes innate immune responses. Our study suggests that dual inhibition of PARP and ATM with nanomedicine is a promising strategy to enhance the pancreatic cancer response to IRE.

In cancer cells with functional ATM and p53 signaling, selective suppression of ATR catalytic activity by M6620 induced G1-phase arrest to prevent S-phase entry with unrepaired DSBs. The selective ATM inhibitors, M3541 and M4076, suppressed both ATM-dependent cell-cycle checkpoints, and DSB repair lowered the p53 protective barrier and extended the life of ATR inhibitor-induced DSBs...ATM inhibitor synergistically potentiated the ATR inhibitor efficacy in cancer cells in vitro and increased ATR inhibitor efficacy in vivo at doses that did not show overt toxicities. Further, a combination study in 26 patient-derived xenograft models of triple negative breast cancer with the newer generation ATR inhibitor M4344 and ATM inhibitor M4076 demonstrated substantial improvement in efficacy and survival compared to single-agent M4344, suggesting a novel and potentially broad combination approach to cancer therapy.

P1, N=67, Not yet recruiting, Mayo Clinic

It showed potent antitumor activity as a single agent or in combination with cisplatin in the human colorectal adenocarcinoma LoVo tumor xenograft mouse model. Overall, ZH-12 may be a promising ATR inhibitor based on the principle of synthetic lethality and deserves further in-depth study.

Moreover, the combination of AZD6738 and AZD0156 induced significantly higher levels of DNA damage than either drug used as single agent alone. In summary, our results demonstrate that targeting ATM is an effective approach to overcome resistance to ATR inhibition in different STS subtypes, including the most frequent histologies.

More importantly, 10q exhibited good liver microsomes stability in different species and also showed moderate inhibitory activity against HT-29 cells in combination treatment with the ATM inhibitor AZD1390. Thus, this work provides a promising lead compound against ATR for further study.

P1, N=48, Recruiting, Memorial Sloan Kettering Cancer Center | Not yet recruiting --> Recruiting | Trial completion date: Mar 2025 --> May 2028 | Trial primary completion date: Mar 2025 --> May 2028

Material and Methods Eight patient derived PDAC cell lines were treated with small molecule inhibitors of ATR (AZD6738 : 20nM - 1µM), PARP (olaparib : 20nM - 1µM) or ATM (AZD1390: 1nM - 100nM) alone and in combination with radiation (0 to 6 Gy). Figure 1 : Survival curves showing radiosensitization of  7 patient derived PDAC cell lines with ATRi(green), ATMi(Blue), PARPi(Red) Figure 2 : Correlation between Replication stress Score and Homologous recombination repair deficiency with ATRi/ATMi  and PARPi radiosensitization Conclusion DDR inhibitors radiosensitized PDAC with the magnitude of radiosensitization depending on Replication Stress and DDR deficiency. These data provide potential therapeutic strategies in the radioresistance setting.

The high expressions of ISG15, IFI27, and OASL were also correlated with complete remission in patients with cervical cancer treated with cisplatin. These results suggest that ATM inhibition can induce the interferon response and inflamed TIME, which may benefit ICB therapy.

No efficacy was detected on cell cycle analysis, and clonogenic survival was not significantly decreased in WI-38 cells. The combination use of irradiation and AZD0156 has improved efficacy of tumor cell-specific cell cycle arrest and decreasing clonogenic survival.

The combination of AZD0156 with staurosporine or vincristine exhibits a synergistic effect on inhibition of refractory/relapsed B-ALL cell survival and leukemia progression in PDX models. Collectively, our study reveals an oncogenic role of the phosphorylated TET1 protein in B-ALL independent of its catalytic activity and highlights the therapeutic potential of targeting TET1 signaling for the treatment of refractory/relapsed B-ALL.

Our study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.