Li, Zhiming

AbstractBackgroundFerroptosis is an important iron‐dependent form of cell death in hepatocellular carcinoma (HCC). Sorafenib, a potent ferroptosis inducer, is used to treat advanced HCC but its efficacy is limited by the development of drug resistance.MethodsThe effects of DUXAP8 expression on HCC progression were evaluated by TCGA database, Kaplan‐Meier analysis, and in situ hybridization analysis. Sorafenib resistant HCC cell lines were modeled in vitro to study the regulation of DUXAP8 on ferroptosis in HCC induced by sorafenib. We used RNA pull‐down, immunofluorescence assays, acyl‐biotinyl exchange assay and mass spectrometry analysis to assess the molecular mechanism of ferroptosis regulation by DUXAP8. Syngeneic subcutaneous and orthotopic CDX models were used to assess whether DUXAP8 inhibition improves HCC in vivo.ResultsLncRNA DUXAP8, which is highly expressed in liver cancer and associated with poor prognosis, contributes to sorafenib resistance through suppression of ferroptosis. In vitro tests revealed that DUXAP8 reduced the sensitivity of HCC to sorafenib‐induced ferroptosis by acting on SLC7A11, a subunit of the amino acid antiporter system xc‐. DUXAP8 facilitates SLC7A11 palmitoylation and impedes its lysosomal degradation, thereby enhancing SLC7A11 action and suppressing ferroptosis. RNA pull‐down and immunofluorescence assays confirmed that DUXAP8 decreased membrane translocation and promoted sorting of de‐palmitoylated SLC7A11 to lysosomes by binding of DUXAP8 to SLC7A11. In addition, mass spectrometric analysis found that the Cys414 residue of SLC7A11 might be the predominant mutant site responsible for molecular masking of SLC7A11 lysosomal sorting. Further, the antitumor effect of DUXAP8 knockdown was verified in orthotopic and subcutaneous CDX models.ConclusionsOur findings suggest that a novel translational strategy combining sorafenib with DUXAP8 silencing to overcome drug resistance may improve treatment efficacy in patients with advanced HCC.

Abstract Background: The dysregulation of polycomb repressive complex 2 (PRC2) promotes tumorigenesis and progression. Two therapeutic agents targeting enhancer of zeste homolog (EZH) 2 or EZH1/2, the catalytic subunits of PRC2, have been approved in several cancer types. HH2853 is a novel selective EZH1/2 dual inhibitor, which has demonstrated superior anti-tumor efficacy to tazemetostat (EZH2 inhibitor approved by FDA) in various preclinical models. Methods: This is a first-in-human, open-label, multi-center, phase (Ph) I/II study of HH2853 in patients (pts) with relapsed/refractory (r/r) non-Hodgkin lymphomas (NHLs) or advanced solid tumors. HH2853 was administered orally twice daily (BID) on a continuous 28-day treatment cycle. Ph I consist of two parts: dose escalation part adopting accelerated titration followed by a Bayesian optimal interval design and dose extension part. Dose limiting toxicity (DLT) was evaluated during the 1st cycle in dose escalation. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of HH2853 were explored in this Ph I study. Results: As of Oct 19, 2022, a total of 57 pts, including 50 pts with solid tumors and 7 pts with r/r follicular lymphoma (FL), were enrolled from 12 sites in China and the US. Twenty-five (43.9%) pts received ≥3 lines of prior systemic therapies. Six dose levels(50 mg, 100 mg, 200 mg, 400 mg, 600 mg and 800 mg)were evaluated. DLTs were observed in 2 of 8 DLT evaluable pts at 800 mg: one grade 3 platelet count decreased and one grade 3 diarrhea. A conclusive maximal tolerated dose was not reached. The most common treatment-related adverse events (TRAE) were diarrhea (45.6%), blood bilirubin increased (35.1%), white blood cell count (WBC) decreased (26.3%), platelet count decreased (26.3%), rash (24.6%) and anemia (22.8%). The most common ≥grade 3 TRAEs included anemia (8.8%), platelet count decreased (7.0%), WBC decreased (5.3%) and diarrhea (5.3%). TRAEs leading to dose interruption or reduction were reported in 17.5% and 8.8% pts respectively. No TRAE led to dose discontinuation or death. PK data indicated dose-related increase in exposure from 50 to 600 mg. PD data showed a significant inhibition (maximum reached >90%) of H3K27me3 in granulocytes and monocytes at 400-800 mg. Tumor responses were observed in 7 pts from 200 to 800 mg in multiple tumor types, including complete response in 1 patient with FL, partial response in 3 pts with epithelioid sarcoma, 2 pts with FL and 1 patient with malignant rhabdoid tumor of pancreas. Conclusions: This first-in-human study of HH2853 showed a manageable safety profile and promising anti-tumor activity in multiple tumor types, supporting further exploration in NHLs and solid tumors after recommended Ph II dose is determined.Clinical trial information: NCT04390737 Citation Format: Zhengfu Fan, Jin Wang, Meiyu Fang, Johnston Patrick, Tun Han, David Sommerhalder, Jifang Gong, Jilong Yang, Yun Yang, Javier Munoz, Yuqin Song, Zhiming Li, Xian'an Li, Qiuying Ma, Jinming Han, Lin Shen, Jun Zhu. Preliminary results from the Phase I part of a first-in-human Phase I/II study of HH2853, an EZH1/2 inhibitor, in patients with relapsed/refractory non-Hodgkin lymphomas or advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT105.