Conversely, PARP inhibitors exhibit selective activity for proliferating cells, providing a mechanism for targeting activity to cancers, but due to poor activity in non-proliferating cells they have an overall reduced impact on tumor growth control. This study highlights the importance of creating a therapeutic ratio with DNA damage repair inhibition radiation sensitizing strategies.

P1/2, N=90, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P1/2, N=98, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

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.

Our findings demonstrate that ARF4-mediated retrograde trafficking contributes to the development of TMZ resistance, cementing this pathway as a viable strategy to overcome chemoresistance in GBM.

P1, N=29, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P1, N=30, Active, not recruiting, Boryung Pharmaceutical Co., Ltd | Recruiting --> Active, not recruiting

P1/2, N=90, Suspended, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

The study suggests that simultaneous inhibition of telomerase and DNA-PK in pre-B ALL presents a novel targeted therapy approach.

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

Moreover, BR101801 exerted robust synergistic effects on IR-induced cell cycle arrest, apoptosis, and tumor growth inhibition, even in radioresistant HCT116 p53 cells. Overall, these findings provide a scientific rationale for combining BR101801 with IR as a new therapeutic strategy to overcome radioresistance induced by p53 deficiency.

P1, N=48, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=36, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting | Initiation date: May 2023 --> Feb 2024

P1/2, N=101, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=29, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1

P1, N=66, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1 | Initiation date: Nov 2023 --> Feb 2024

In conclusion, AZD7648 synergistically increased radiosensitivity through accumulating IR-induced G2/M arrest and further improved radioresistance via regulation of HIF-1α. The present data suggest that AZD7648 may be a strong radiosensitizer in radioresistant as well as radiosensitive cancers.

P1/2, N=90, Suspended, National Cancer Institute (NCI) | Phase classification: P2 --> P1/2

PRKDC inhibition with nedisertib sensitized glioblastomas to radiotherapy and extended survival in vivo, and single-cell RNA sequencing revealed hyperactivation of cell stress and cytokine signatures with combination treatment. In summary, we report in vivo perturb-seq as a platform for simultaneous discovery and functional interrogation of therapeutic vulnerabilities in glioblastoma, and show DNA-PK inhibition sensitizes glioblastomas to radiotherapy in vivo.

Both groups receive adjuvant temozolomide for 6-cycles. The initial safety data of peposertib plus radiation in newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors with DDR mutations, the gain of two ATM mutations in a recurrent tumor and the cases of scalp dermatitis suggest that peposertib is active and possibly potentiates the effect of radiation. Safety and survival data and correlations with genomics will be presented.

INSIGhT (NCT02977780) is an ongoing phase 2 adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma with a shared control arm of patients receiving radiation therapy with concurrent and maintenance temozolomide. In comparison to an ECA, there was no significant survival benefit with abemaciclib, neratinib and CC-115. Treatment effects estimates were similar to the primary analyses based on the original shared control arm of INSIGhT. The use of external control arms in early phase testing of new therapies is supported by our findings and could significantly reduce costs and time to conduct trials in newly diagnosed glioblastoma.

AZD7648 reduced the MOI needed for viral transduction by 50% while maintaining 80% or higher levels of transgene knock-in efficiency...We show that metabolic reprogramming can be combined with precision genome editing to generate controllable CART cells. Finally, our data demonstrate the feasibility of automating CRISPR/Cas9-mediated engineering of CAR T cells within closed-system.

Preliminary results showed the ORR of 31.6% and a CR rate of 21.1%. Phase 2 study is warranted further investigate the safety and efficacy of BR101801 in r/r PTCL and Nodal TFH cell lymphoma at 200 mg QD orally.

P2, N=90, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

Besides the reduction in cell proliferation, AZD-7648 induced apoptosis, cell cycle arrest, and DNA damage. In conclusion, these results suggest that AZD-7648 holds promise as a potential therapy for myeloid leukemias, however, with variations in drug sensitivity among tested cell lines, thus supporting further investigation to identify the specific factors influencing sensitivity to this DNA-PK inhibitor.

P1, N=29, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2023 --> Oct 2025 | Trial primary completion date: Oct 2023 --> Oct 2025

P1b, N=66, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting | Initiation date: May 2023 --> Nov 2023

In SSTR2-positive xenograft-bearing mice, the combination of nedisertib (a DNA-PK specific inhibitor) and LuTate produced a more robust control of tumour growth and increased survival compared to LuTate alone. DDR pathways are critical for sensing and repairing radiation-induced DNA damage, and our study shows that regulation of DDR pathways may be involved in both resistance and sensitivity to PRRT. Additionally, the use of a DNA-PK inhibitor in combination with LuTate PRRT significantly improves the efficacy of the treatment in pre-clinical models, providing further evidence for the clinical efficacy of this combination.

Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS.

Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg QD as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure.

The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

This ongoing phase 1 dose escalation and dose expansion study is evaluating low dose liposomal doxorubicin combined with the DNA-PK inhibitor peposertib in LMS and select STS with embedded correlative studies to identify predictive biomarkers and explore mechanism of action. Note: Research support for correlative studies and peposertib supply were provided by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

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

P1, N=20, Completed, Stemline Therapeutics, Inc. | Recruiting --> Completed | N=60 --> 20 | Trial completion date: Dec 2023 --> Jun 2023 | Trial primary completion date: Dec 2023 --> May 2023

Furthermore, BI-2536, camptothecin and NU7441 were identified as possible drug candidates in the high-risk group. We constructed a predictive model for ESCC based on TCA cycle-associated genes, which achieved good prognostic stratification. The model are likely associated with the regulation of tumor immunity in ESCC.

P1, N=36, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

We analyzed effects of combining PRRT and DNA-PKcs inhibitor AZD7648 on viability, cell death and clonogenic survival on SSTR2-expressing cell lines BON1-SSTR2, GOT1 and NCI-H69... These results highlight that the potentiation of the therapeutic effect of PRRT by DNA-PKcs inhibition is a highly effective and well-tolerated therapeutic strategy. Based on our findings, we recommend initiation of phase I/II studies in patients to find a safe and effective combination regimen.

P1b, N=66, Suspended, National Cancer Institute (NCI) | Not yet recruiting --> Suspended

This inhibitor increased the percentage of apoptotic cells and the levels of activated caspase-3 and cleaved PARP, induced cell cycle arrest in G0/G1 phase, and reduced cell proliferation. DNA and chromosomal damage levels increased after incubation with AZD-7648.ConclusionIn conclusion, our results demonstrated the efficacy of AZD-7648 on AML models, thus supporting further investigation of the potential of this inhibitor as a new therapy in AML that may ultimately improve the outcome of AML patients.

Importantly, CC-115 significantly upregulated the expression of Bax and GSDME-N in a xenograft mouse model, with a reduction in tumor size. Our results revealed that CC-115 suppresses tumor growth by inducing GSDME-mediated pyroptosis through the Akt/Bax-mitochondrial intrinsic pathway, indicating CC-115 as a promising therapeutic agent for LUAD.

P1b, N=29, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Jun 2024