P2 exhibited a ∼10-fold increase in antiproliferative potency against human leukemic cell lines compared to homoharringtonine (HHT)...Our findings provide valuable insights to guide the future structural optimization of harringtonine derivatives. Furthermore, P2 has been identified as a promising anti-leukemic candidate and warrants further development.

In vivo, the anti-leukemic efficacy of HHT was significantly diminished upon EWSR1 knockdown, demonstrating that EWSR1 was required for therapeutic response. Collectively, these findings uncover a phase separation-centric mechanism by which HHT exerts anti-AML activity, establish the EWSR1-YTHDF2-m6A axis as a critical regulator of leukemia progression, and position EWSR1 as both a functional target and a predictive biomarker for optimizing HHT-based therapies.

This study highlights the value of computational drug repurposing platforms for accelerating therapeutic discovery. Further preclinical investigations are warranted to evaluate HHT's in vivo efficacy and clinical applicability in RPF.

Our study demonstrates the utility of cancer organoids in drug discovery and identifies HHT as a promising therapeuticagent for ATC.

P1/2, N=28, Active, not recruiting, University of Colorado, Denver | Trial primary completion date: Aug 2026 --> Oct 2025

Infiltrative mediastinal/retroperitoneal MS may present with esophageal obstruction and mimic lymphoma or carcinoma. High-index suspicion, targeted biopsy with high-power morphology, and a focused immunohistochemical panel are critical for timely diagnosis and treatment initiation.

P1/2, N=24, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; The study terminated early because the company was longer providing the investigational product.

We then evaluated the response of these mutant cells to a panel of compounds targeting protein synthesis at various levels-including an MNK1 inhibitor, metformin, silvestrol, homoharringtonine, anisomycin, resveratrol, and hygromycin B-as well as cytarabine, a chemotherapeutic agent commonly used in T-ALL treatment. Our results showed that the RPL5-I60V mutation confers increased sensitivity to most of these compounds, with the exception of hygromycin B. This study advances our understanding of how oncoribosomes contribute to cancer pathogenesis and highlights the therapeutic potential of directly or indirectly targeting altered ribosomes, offering insights for the development of personalized treatment strategies.

P1/2, N=62, Not yet recruiting, The First Affiliated Hospital, Zhejiang University College of Medicine; The First Affiliated Hospital of Zhejiang University Medical College

P1/2, N=28, Active, not recruiting, University of Colorado, Denver | Trial primary completion date: Aug 2025 --> Aug 2026

Clinical responses were seen exclusively in patients with MDS, which suggests that dose optimization or combination with cytoreductive agents may be necessary for eliciting clinical activity in AML. This trial was registered at www.ClinicalTrials.gov as #NCT04874194.

P1/2, N=62, Not yet recruiting, First Affiliated Hospital of Zhejiang University