bims-necame 2025-09-28 papers

Issue of 2025–09–28
three papers selected by
Grigor Varuzhanyan, UCLA

Mol Cancer Ther. 2025 Sep 25. OF1-OF13

CRISPR Screen Identifies HDAC3 as a Novel Radiosensitizing Target in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive malignancy, with most patients presenting with prognostically poor extensive-stage disease. Limited progress in standard care stresses the urgent need for novel therapies. Radiotherapy offers some survival benefit for selected patients with SCLC but could be enhanced with radiosensitizers. In this study, we identify HDAC3 as a novel radiosensitizing target in SCLC using a CRISPR knockout screen and demonstrate its efficacy and mechanism. SBC5 cells were transduced with a custom EpiDrug single-guide RNA library and treated with ionizing radiation (IR) to identify radiosensitizing genes. HDAC3 emerged as a candidate and was validated through genetic knockdown and pharmacologic inhibition (RGFP966) in multiple SCLC cell lines. Both approaches enhanced radiosensitivity, as shown by cell viability (dose modification factor10 = 1.14-1.69) and clonogenic assays (dose modification factor10 = 1.16-1.41). We assessed changes in chromatin accessibility by assay for transposase-accessible chromatin using sequencing and IR-induced DNA damage and repair using γH2AX foci detection, double-strand break (DSB) repair assays, and immunoblotting of repair proteins. HDAC3-deficient cells exhibited increased chromatin accessibility, greater IR-induced DSBs, and impaired repair capacity, resulting in persistent DNA damage. This repair defect sensitized cells to PARP inhibitors, for which combining RGFP966 with olaparib or talazoparib produced additive to synergistic effects. In SCLC xenograft models, HDAC3 knockdown or RGFP966, combined with IR, achieved significant tumor growth inhibition. Collectively, we identified HDAC3 as a novel radiosensitizing target in SCLC. Its functional loss increased the generation and persistence of IR-induced DNA DSBs, effectively sensitizing SCLC cell lines and xenografts to IR, providing a potential radiosensitization strategy to treat SCLC.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0861

J Pharmacol Exp Ther. 2025 Aug 28. pii: S0022-3565(25)39897-6. [Epub ahead of print]392(10): 103684

Koningic acid reduces tumor activity in neuroendocrine prostate cancer by inhibiting glycolysis.

Haixia Xu, Liang Xiao, Lin Lin, Meixiang Li, Yunting Yang, Jiajian Lin, Lili Jiang, Yi Yang.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer with poor prognosis and limited therapeutic options. Targeting cancer metabolism is a promising strategy for treating NEPC. This study investigated the antitumor activity and underlying mechanisms of koningic acid (KA), a selective glyceraldehyde-3-phosphate dehydrogenase inhibitor, in NEPC. NEPC cell models (PC3, LNCaP-NE, and NCI-H660) were treated with KA to assess its effects on cell viability, colony formation, glycolysis, mitochondrial function, and apoptosis. Xenograft models were used to evaluate in vivo tumor growth. Key markers and pathways were analyzed using quantitative polymerase chain reaction, western blotting, and immunohistochemistry. In this study, KA significantly inhibited cell proliferation and colony formation, with IC50 values of 5.73 μM in PC3, 7.57 μM in LNCaP-NE, and 6.32 μM in NCI-H660 cells. Glycolysis was markedly suppressed, as indicated by reduced extracellular acidification rate, lactate production, and glucose uptake. KA also induced mitochondrial dysfunction, evidenced by decreased mitochondrial membrane potential, increased reactive oxygen species, and reduced ATP levels. Furthermore, KA decreased phospho (p)-Akt and p-glycogen synthase kinase-3β expression, leading to apoptosis activation. In xenograft models, KA treatment reduced tumor size, weight, and expression of Ki67, p-Akt, and of lactate dehydrogenase A, while increasing levels of apoptosis markers. In conclusion, KA exerts significant antitumor effects in NEPC by inhibiting glycolysis and inducing mitochondrial apoptosis. These findings highlight its potential as a therapeutic agent for NEPC. SIGNIFICANCE STATEMENT: Koningic acid (KA) inhibits glycolysis and suppresses proliferation in neuroendocrine prostate cancer cells by targeting glyceraldehyde-3-phosphate dehydrogenase. KA induces mitochondrial dysfunction, increases reactive oxygen species production, and activates apoptosis through downregulation of phospho-Akt and phospho-glycogen synthase kinase-3β signaling. In vivo studies demonstrate that KA reduces tumor growth and proliferation while promoting apoptosis, highlighting its potential as a therapeutic agent for neuroendocrine prostate cancer.

Keywords: Glycolysis; Koningic acid; Mitochondrial apoptosis; Neuroendocrine prostate cancer

DOI: https://doi.org/10.1016/j.jpet.2025.103684

Eur J Radiol. 2025 Sep 19. pii: S0720-048X(25)00511-X. [Epub ahead of print]193 112425

Development and validation of multiparametric models incorporating 18F-FDG PET/CT dissemination characteristic for predicting outcomes of small cell lung cancer.

Yang Liu, Xin Zhou, Xiangxi Meng, Xiangxing Kong, Changzhi Du, Yan Cui, Yitong Liu, Jinyu Zhu, Yuan Yao, Chunxu Cao, Min Wang, Nan Li.

OBJECTIVE: To evaluate the prognostic value of the tumor dissemination characteristic, metabolic parameters from baseline 18F-FDG PET/CT, clinical indicators, and pathological indicators in small cell lung cancer (SCLC), and to construct prognostic models.
MATERIALS & METHODS: SCLC patients who underwent baseline 18F-FDG PET/CT were retrospectively analyzed and randomly divided into training and validation cohorts (7:3). The tumor dissemination characteristic, metabolic characteristics, morphological features, and clinical and pathological indicators were collected. Cox regression analysis was employed to identify independent prognostic factors. Prognostic models and corresponding nomograms were developed and evaluated using receiver operating characteristic (ROC) curves.
RESULTS: 303 patients with SCLC were enrolled (including 204 males and 99 females; median age: 62 years, interquartile range: 56-67 years). Multivariate Cox regression analysis identified age, stage, neuron-specific enolase (NSE), and the standardized distance between the two farthest lesions (SDmax) as independent prognostic factors for progression-free survival (PFS). Area under curve (AUC) values for predicting 6-month, 12-month, and 24-month PFS were 0.790, 0.778, and 0.750 in the training cohort, and 0.778, 0.771, and 0.744 in the validation cohort. For overall survival (OS), age, stage, NSE, whole-body metabolic tumor volume (MTVwb), and SDmax were independent prognostic factors. AUC values for predicting 1-year, 2-year, and 3-year OS were 0.861, 0.830, and 0.799 in the training cohort, and 0.834, 0.801, and 0.787 in the validation cohort.
CONCLUSION: The tumor dissemination characteristic from baseline 18F-FDG PET/CT is a novel independent prognostic factor in SCLC. Additionally, the models incorporating the dissemination characteristic, metabolic parameter, and clinical indicators demonstrate excellent predictive capabilities in SCLC.

Keywords: (18)F-FDG PET/CT; Dissemination characteristic; Metabolic characteristic; Prognosis; Small cell lung cancer

DOI: https://doi.org/10.1016/j.ejrad.2025.112425