P1, N=29, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Jun 2026 | Trial primary completion date: Oct 2025 --> Jun 2026

In the syngeneic CT26 model, dual PI3Kδ/γ inhibition (BR101801 or duvelisib), unlike selective PI3Kδ inhibition (idelalisib), synergized with RT (7.5 Gy) to suppress tumor growth and induce durable immune memory. Furthermore, blockade of the IFN-I receptor abolished CD8+ T cell infiltration and M2-like macrophage suppression, abrogating antitumor efficacy and confirming the requirement for IFN-I signaling. These findings identify macrophage-driven activation of the cGAS-STING-IFN-I axis as a key mechanism by which dual PI3Kδ/γ inhibition potentiates RT, providing a strong scientific rationale for its development as an immunomodulatory radiosensitizer.

P1/2, N=103, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1/2, N=123, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

This study identifies ATT-1 as a promising multi-targeted therapeutic for colorectal cancer by leveraging PDOs for direct, de novo target discovery. We uniquely identified two novel, high-affinity targets, CLTC and XRCC5, and elucidated a convergent dual-targeting mechanism wherein ATT-1 binding disrupts DNA damage repair and triggers apoptosis. This novel mechanism and its potent synergy with standard chemotherapy in physiologically relevant models provide a compelling strategy for integrating traditional Chinese medicine into modern precision oncology.

Glioblastoma (GBM) remains one of the deadliest primary brain tumors, with rapid recurrence and near-universal resistance to temozolomide (TMZ) limiting long-term survival...Inhibition of PRKDC with the ATP-competitive inhibitor KU57788 reversed resistance, restoring TMZ sensitivity and impairing tumor growth in vivo...These results establish the LMNA-PRKDC axis as a functional driver of TMZ resistance through enhanced DNA repair capacity in stem-like tumor subpopulations. Our findings support pharmacologic inhibition of PRKDC as a rational strategy to resensitize resistant GBM to standard chemotherapy and offer a foundation for future biomarker-driven clinical trials targeting DNA repair vulnerabilities in recurrent disease.

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.

P1/2, N=123, Not yet recruiting, Novartis Pharmaceuticals

When combined with the DNA damage repair inhibitor AZD7648 to enhance immunogenic cell death (ICD), the MPD1-based therapy triggered robust pyroptosis and upregulated ICD markers on tumor cells...Rechallenge studies confirmed the establishment of robust immunological memory. This work establishes a new engineering paradigm with a self-amplifying, ICD-inducing therapy for treating historically "undruggable" cancers, creating a strategy to convert resistant tumors into ones that are highly susceptible to immunotherapy with clinically usable drugs.

Drug sensitivity analysis revealed that high-PCDS patients may benefit more from agents like sorafenib and fulvestrant, while low-PCDS patients responded better to NU7441. Notably, the PCDS is closely associated with key immunological characteristics of the TME. These findings advance personalized treatment strategies and support clinically relevant decision-making in DLBCL.

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

P2, N=44, Not yet recruiting, Boryung Pharmaceutical Co., Ltd