Multiple myeloma (MM) is an incurable malignant hematological neoplasm characterized by clonal proliferation of plasma cells accumulating in the bone marrow. Currently, the treatment of MM is usually based on a multi-drug combination strategy, and the remission rates of MM patients have been greatly improved. However, MM is still not immune to drug resistance and recurrence and is an incurable tumor. In this study, a comprehensive screen of the TCA cycle identified oxoglutarate dehydrogenase (OGDH) and pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) as the most clinically relevant genes in MM, highlighting their potential as therapeutic targets. CPI-613, a novel non-redox-active lipoic acid analog that causes mitochondrial metabolism dysfunction by targeting OGDH and PDHA1, is currently in clinical trials in a variety of malignancies. In our study, CPI-613 was found to inhibit the proliferation of MM cells, and its combination with bortezomib (BTZ) produced a significant inhibitory effect at lower doses. In addition, CPI-613 can disrupt various mitochondrial functions, such as disrupting mitochondrial morphology, reducing oxidative phosphorylation, decreasing 5'- adenylate triphosphate production, and increasing reactive oxygen species, which ultimately leads to cell death mediated by the intrinsic apoptotic pathway in vitro. Furthermore, we found CPI-613 significantly inhibited tumor growth and induced intrinsic apoptosis in the MM mouse xenograft model. This study reveals the mechanism and effect of CPI-613 in MM, which suggests that CPI-613 may be a new drug option for the clinical treatment of MM, but further clinical trials are needed for evaluation.

Adipose tissue remodels via hypertrophy or hyperplasia in response to nutrient status, but the mechanisms governing these expansion modes remain unclear. Here, we identify a nutrient-sensitive epigenetic circuit linking glucose metabolism to chromatin remodeling during adipogenesis. Upon glucose stimulation, α-ketoglutarate (α-KG) accumulates in the nucleus and activates the histone demethylase JMJD1A to remove repressive histone H3 lysine 9 dimethylation (H3K9me2) marks at glycolytic and adipogenic gene loci, including Pparg. JMJD1A is recruited to pre-marked promoter chromatin via nuclear factor IC (NFIC), enabling carbohydrate-responsive element-binding protein (ChREBP) binding and transcriptional activation. This feedforward mechanism couples nutrient flux to chromatin accessibility and gene expression. In vivo, JMJD1A is essential for de novo adipogenesis and hyperplastic expansion in visceral fat under nutrient excess. JMJD1A deficiency impairs hyperplasia, exacerbates adipocyte hypertrophy, and induces local inflammation. These findings define a glucose-α-KG-JMJD1A-ChREBP axis regulating depot-specific adipogenesis and uncover a chromatin-based mechanism by which glucose metabolism governs adaptive adipose tissue remodeling.

Glioma-associated macrophages (GAMs) are central mediators of immune evasion and therapeutic resistance in glioblastoma multiforme (GBM) due to their tumor-promoting M2 phenotype and loss of phagocytic activity toward tumor cells. Activating GAMs represent an attractive therapeutic strategy against GBM, but it is hindered by the lack of effective therapies and insufficient drug exposure. Herein, an engineered biomimetic delivery system (SIRPα@BSA/PTX) is developed by enveloping albumin-bound paclitaxel (BSA/PTX) with a genetically engineered melanoma cell membrane expressing SIRPα variants to activate GAMs for improved GBM therapy. SIRPα@BSA/PTX efficiently penetrates the blood-brain barrier (BBB) to accumulate in GBM by leveraging the brain tropism of the melanoma cell membrane. Subsequently, SIRPα variants on the cell membrane, along with PTX in the inner core, synergistically enhance the repolarization and phagocytic abilities of GAMs. In vivo studies show that SIRPα@BSA/PTX significantly suppresses tumor growth and recurrence in orthotopic and postoperative murine GBM models and achieves 100% mouse survival when combined with immune checkpoint inhibitors. Transcriptome analysis of clinical GBM patient samples treated with SIRPα@BSA/PTX also reveals remarkable immune activation signatures, suggesting the great potential of nanoenabled macrophage-based immunotherapy for brain tumors.

ObjectivesTo evaluate the performance of stool methylated syndecan2 (mSDC2), methylated septin9 (mSEPT9), fecal occult blood test (FOBT), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125) and carbohydrate antigen 199 (CA199) in detecting colorectal neoplasia and adenomas.MethodsBlood-borne CEA, CA125, and CA199 levels were measured by electrochemiluminescence. The SDC2 methylation was detected by Methylation Detection Kit for Human SDC2 Gene (Real time PCR), and the SEPT9 methylation was detected by the Septin9 Gene Methylation Detection Kit based on PCR fluorescent probe assay. The colonoscopy combined with tissue biopsy pathology was used as a validation criterion for colorectal neoplasia.ResultsIn detecting colorectal neoplasia, the AUCs of mSDC2, FOBT and mSEPT9 were 0.935 (95% CI: 0.915-0.956, P<0.001), 0.824 (95% CI: 0.617-1.000, P<0.001) and 0.671 (95% CI: 0.511-0.831, P<0.001), respectively. The sensitivity of mSDC2, FOBT and mSEPT9 were 100.0%, 66.7% and 40.0%, respectively. But the AUC of CEA, CA125 and CA199 were not statistically significant for colorectal neoplasia (all P>0.05). The combined application of mSEPT9 and mSDC2 showed the best predictive performance (AUC: 0.956, 95% CI: 0.887~1.000). For adenomas, the AUC of FOBT was extremely low (AUC: 0.524, 95% CI: 0.502-0.545, P=0.004). The CEA, CA125, CA199, mSEPT9 and mSDC2 were not statistically significant in detecting adenomas (all P>0.05).ConclusionsFor individual tests, FOBT and mSDC2 are relatively better indicators for detecting colorectal neoplasia compared to mSEPT9, CEA, CA125 and CA199. The combined form of mSEPT9 and mSDC2 to detect colorectal neoplasia has good predictive performance. However, none of these indicators demonstrated significant predictive power for detecting adenomas in our study.

Non‑small cell lung cancer (NSCLC) is one of the major causes of cancer‑related death worldwide. Cisplatin is a front‑line chemotherapeutic agent in NSCLC. Nevertheless, subsequent harsh side effects and drug resistance limit its further clinical application. Polydatin (PD) induces apoptosis in various cancer cells by generating reactive oxygen species (ROS). However, underlying molecular mechanisms of PD and its effects on cisplatin‑mediated antitumor activity in NSCLC remains unknown. MTT, colony formation, wound healing analyses and flow cytometry was employed to investigate the cell phenotypic changes and ROS generation. Relative gene and protein expressions were evaluated by reverse transcription‑quantitative PCR and western blot analyses. The antitumor effects of PD, cisplatin and their combination were evaluated by mouse xenograft model. In the present study, it was found that PD in combination with cisplatin synergistically enhances the antitumor activity in NSCLC by stimulating ROS‑mediated endoplasmic reticulum stress, and the C‑Jun‑amino‑terminal kinase and p38 mitogen‑activated protein kinase signaling pathways. PD treatment elevated ROS generation by promoting expression of NADPH oxidase 5 (NOX5), and NOX5 knockdown attenuated ROS‑mediated cytotoxicity of PD in NSCLC cells. Mice xenograft model further confirmed the synergistic antitumor efficacy of combined therapy with PD and cisplatin. The present study exhibited a superior therapeutic strategy for some patients with NSCLC by combining PD and cisplatin.

Abstract Background: Therapeutics targeting PD-(L)1 have demonstrated impressive clinical activity in several type of cancers. However, only a small proportion of patients develop long-term response and resistance frequently occurs. LAG-3 and TIM-3 are inhibitory immune checkpoints frequently upregulated and co-expressed with PD-1 on tumor-infiltrating T cells, contributing to T cell dysfunction. Thus, we hypothesized that simultaneously targeting PD-1/LAG-3/TIM-3 would further restore T cell response and the triple combination of Tislelizumab (Tisle, anti-PD-1), LBL-007 (anti-LAG-3) and Surzebiclimab (Surze, anti-TIM-3) would provide greater clinical benefit.Methods: To evaluate the rationale and the anti-tumor activity of triple combination, LAG-3 and TIM-3 expression were analyzed in in vitro T cells, syngeneic mouse models and cancer patients with anti-PD-(L)1 therapy. The effects of dual blockade of PD-1/LAG-3, PD-1/TIM-3 and the triple blockade of PD-1/LAG-3/TIM-3 on T cell function were evaluated in in vitro activated PBMCs and the anti-tumor efficacy were evaluated in syngeneic mouse models. Relevant gene expression and immune signatures were ranked across 31 solid tumor types in TCGA.Results: Both LAG-3 and TIM-3 expression on T cells were upregulated by anti-PD-1 treatment in syngeneic mouse tumors, similar trend was observed in cancer patients with anti-PD-(L)1 therapy. Dual combination of Tisle/LBL-007 or Tisle/Surze enhanced IFNγ production in in vitro activated human T cells. The dual blockade of PD-1/LAG-3 or PD-1/TIM-3 significantly enhanced tumor growth inhibition compared with anti-PD-1 monotherapy in syngeneic mouse models. The triple combination of Tisle/LBL-007/Surze further enhanced IFNγ production in in vitro activated T cells. In a mouse MC38 colon carcinoma model, the triple blockade of PD-1/LAG-3/TIM-3 demonstrated enhanced anti-tumor activity compared with either dual combination, evidenced by trend of increased tumor growth inhibition and higher tumor-free incidence rate. Finally, the responsiveness of PD-1/LAG-3/TIM-3 triple combination was predicted using 5 signatures, including early effector T cell signature, inflamed signature, LAG-3, TIM-3 and PD-L1 expression. The in silico analyses indicated strong potential in clinical utility such as squamous cell carcinoma of the head and neck (HNSCC).Conclusions: The concurrent blockade of PD-1/LAG-3/TIM-3 represents a promising strategy to enhance T cell function and anti-tumor activity. The results demonstrated the therapeutic potential of the triple combination. A Ph2 study evaluating Tisle in combination with LBL-007 and/or Surze in first-line treatment of recurrent or metastatic HNSCC (NCT05909904) is recruiting. Citation Format: Hengrui Zhu, Jinhui Zhang, Han Yan, Xiao Ding, Juan Yang, Yu Jiang, Minjuan Deng, Haoxuan Song, Fangfang Ping, Fuyun Sun, Xiaoyu Li, Lijie Zhang, Bin Jiang, Weiwei Song, Zhirong Shen, Wei Jin, Jiyuan Zhang, Yun Zhang. Translational assessment of triple combination with Tislelizumab (anti-PD-1), LBL-007 (anti-LAG-3) and < for Surzebiclimab (anti-TIM-3) highlights its strong anti-tumor activity and < for clinical potential in solid tumors such as HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4041.

Dihydroartemisinin (DHA) exerts an anti-tumor effect in multiple cancers, however, the molecular mechanism of DHA and whether DHA facilitates the anti-tumor efficacy of cisplatin in non-small cell lung cancer (NSCLC) are unclear. Here, we found that DHA potentiated the anti-tumor effects of cisplatin in NSCLC cells by stimulating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 MAPK signaling pathways both in vitro and in vivo. Of note, we demonstrated for the first time that DHA inhibits prostaglandin G/H synthase 1 (PTGS1) expression, resulting in enhanced ROS production. Importantly, silencing PTGS1 sensitized DHA-induced cell death by increasing ROS production and activating ER-stress, JNK and p38 MAPK signaling pathways. In summary, our findings provided new experimental basis and therapeutic prospect for the combined therapy with DHA and cisplatin in some NSCLC patients.

SARS-CoV-2 papain-like protease (PLpro) could facilitate viral replication and host immune evasion by respectively hydrolyzing viral polyprotein and host ubiquitin conjugates, thereby rendering itself as an important antiviral target. Yet few noncovalent PLpro inhibitors of SARS-CoV-2 have been reported with improved directed towards pathogenic deubiquitinating activities inhibition. Herein, we report that coronavirus PLpro proteases have distinctive substrate bias and are conserved to deubiquitylate K63-linked polyubiquitination, thereby attenuating host type I interferon response. We identify a noncovalent compound specifically optimized towards halting the K63-deubiquitinase activity of SARS-CoV-2 PLpro, but not other coronavirus (CoV) counterparts or host deubiquitinase. Contrasting with GRL-0617, a SARS-CoV-1 PLpro inhibitor, SIMM-036 is 50-fold and 7-fold (half maximal inhibitory concentration (IC50)) more potent to inhibit viral replication during SARS-CoV-2 infection and restore the host interferon-β (IFN-β) response in human angiotensin-converting enzyme 2 (hACE2)-HeLa cells, respectively. Structure-activity relationship (SAR) analysis further reveals the importance of BL2 groove of PLpro, which could determine the selectivity of K63-deubiquitinase activity of the enzyme.

Colorectal cancer (CRC) is the third most common cancer, and is one of the leading causes of cancer-related death worldwide. At the time of diagnosis, about 20% of patients with CRC present metastatic disease. Regorafenib, an oral multi-kinase inhibitor, has been demonstrated the efficacy and tolerability in patients with metastatic CRC. Oxaliplatin is a frontline treatment regimen for CRC, and combination treatments with oxaliplatin and other chemotherapeutic agents exert superior therapeutic effects. However, side effects and drug resistance limited their further clinical application. Here, we found that combined treatment with regorafenib and oxaliplatin synergistically enhanced anti-tumor activities in CRC by activating reactive oxygen species (ROS) mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 signaling pathways. Regorafenib promoted ROS production by suppressing the expression of selenoprotein S (SELENOS). Knocking down SELENOS sensitized ROS-mediated anti-tumor effects of regorafenib in CRC cells. Furthermore, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with regorafenib and oxaliplatin. This study provided solid experimental evidences for the combined treatment with regorafenib and oxaliplatin in CRC.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 (IDH1) induce extensive transcriptional alterations to promote glioma development. However, IDH1 mutation contributes the better clinical outcomes of glioma. Further -nderstanding the transcriptional and DNA methylation changes mediated by IDH1 mutation will provide new therapeutic targets for glioma.METHODS: Public glioma cohorts were collected and processed using R software. The transcriptional changes mediated by IDH1 mutation were determined and presented using heatmap. The differentially expressed genes in IDH1 mutant glioma were overlapped using TBtools. The prog-nostic effects of IDH1 regulated genes were determined by Kaplan-Meier survival analysis.RESULTS: Retinoic acid receptor responder 2 (RARRES2) was upregulated in IDH1 wild type lower-grade glioma (LGG) patients, and higher expression levels of RARRES2 were associated with worse clinical outcomes of LGG. Moreover, IDH1 wild type LGG patients with higher expression levels of RARRES2 had even worse overall survival. Compared with LGG, RARRES2 was upregulated in grade IV glioma (glioblastoma multiforme, GBM). Also, RARRES2 represented an unfavorable prognostic factor of glioma. In GBM, RARRES2 was also associated with IDH1 mutation. In both LGG and GBM, IDH1 mutation induced extensive DNA hypermethylation, and more than half genes that were downregulated in IDH1 mutant glioma werecontributed by DNA hypermethylation. RARRES2 was also hypermethylated in IDH1 mutant LGG or GBM patients. Furthermore, RARRES2 hypomethylation was an unfavor-able prognostic factor in patients with LGG.CONCLUSIONS: RARRES2 was downregulated by IDH1 mutation and served as an unfavorable prognostic factor in glioma.

The molecular heterogeneity of primary clear cell renal cell carcinoma (ccRCC) has been reported. However, the classifications of Von Hippel-Lindau (VHL) mutant ccRCC are unclear. Here, VHL mutant ccRCC from The Cancer Genome Atlas and E-MTAB-1980 datasets were divided into two sub-clusters through non-negative matrix factorization algorithm. Most VHL mutant ccRCC patients in sub-cluster2 were with pathological T1 stage and VHL mutant ccRCC patients in sub-cluster1 were with decreased overall survival. DNA replication and homologous recombination scores were higher, while, WNT signaling pathway and regulation of autophagy scores were lower in sub-cluster1 VHL mutant ccRCC. Moreover, PBX1 transcriptional scores and mRNA expressions were lower in sub-cluster1 VHL mutant ccRCC patients and were associated with the overall survival of VHL mutant ccRCC. Furthermore, PBX1 associated genes EMCN and ERG were down-regulated in sub-cluster1 VHL mutant ccRCC and overall survival was decreased in EMCN or ERG lowly expressed VHL mutant ccRCC patients. Also, PBX1 and EMCN were down-regulated in ccRCC tissues, compared with normal kidney tissues. At last, we constructed risk models based on PBX1, EMCN and EGR expression features. With the increase of the risk score, the number of death of VHL mutant ccRCC patients was increased.

AbstractBackgroundA subgroup of glioma carry genetic 4q12 amplification including platelet derived growth factor receptor α (PDGFRA) and insulin like growth factor binding protein 7 (IGFBP7). However, the prognosis of PDGFRA and IGFBP7 in glioma is unclear.MethodsThe prognosis of PDGFRA and IGFBP7 was determined using cox regression and Kaplan–Meier survival analysis. Pathways associated with IGFBP7 were analyzed through gene set enrichment analysis (GSEA). Immune profiling of glioma was determined using “ESTIMATE” and “TIMER” database.ResultsPDGFRA amplification or expression was not correlated with the outcomes of glioblastoma (GBM). IGFBP7 but not PDGFRA was over‐expressed in GBM. IGFBP7 over‐expression was correlated with the unfavorable outcomes of GBM. In lower grade glioma (LGG), PDGFRA over‐expression was not correlated with the unfavorable prognosis of LGG, while, IGFBP7 was a prognostic biomarker of LGG. LGG patients with IGFBP7 lower expressions had prolonged clinical overall survival. Combination of IDH mutation, LGG grade and IGFBP7 achieved even better prognostic effects in LGG. Moreover, IGFBP7 was over‐expressed in glioma patients with wild type IDH or with high grades. IGFBP7 over‐expression was correlated with the unfavorable outcomes of glioma. Furthermore, IGFBP7 was hypo‐methylated in GBM or LGG patients without IDH mutations. IGFBP7 hyper‐methylation was correlated with the lower overall survival of GBM or LGG. LGG patients with wild type IDH and with IGFBP7 hypo‐methylation demonstrated even worse prognosis. IGFBP7 was associated with multiple immune‐related signaling pathways in GBM or LGG. The stromal score, immune score and the infiltrations of immune cells were also correlated with IGFBP7 and the prognosis of LGG.ConclusionsIGFBP7 but not PDGFRA served an ideal prognostic marker and therapeutic target of glioma.

Arsenic trioxide (ATO) has been shown to be effective in treating acute promyelocytic leukemia. TP53 mutated/null tumor cells are more sensitive to ATO treatment compared to tumor cells carrying wildtype TP53 gene copies. However, it is unclear whether TP53 inhibitors can increase the sensitivity of TP53 wildtype tumor cells to ATO. Here we show that breast, colon, and lung cancer cell lines with mutated/null TP53 are more sensitive to ATO‐induced cell growth inhibition than cells with wildtype TP53. Moreover, inhibition of TP53 by a TP53 inhibitor, PFTα, increased the ATO sensitivity of TP53 wildtype tumor cells, coincident with ATO‐induced cell growth arrest and cell apoptosis. Furthermore, combined treatment with ATO and PFTα synergistically inhibited tumor growth in mouse xenografts in vivo. Through microarray transcriptional analysis, we found that ATO‐regulated genes were associated with TP53 and cell cycle signaling pathways. Cotreatment with PFTα enhanced ATO‐induced dynamic transcriptional changes. Overall, our results provide evidence for using TP53 chemical inhibitors to enhance the ATO‐mediated therapeutic response against TP53 wildtype tumor cells.

Background Previously, we had analyzed the prognosis of E2F transcription factors across adult tumor types. However, the expressions and prognosis of E2F transcription factors in pediatric neuroblastoma have not yet been fully studied. Methods The prognosis of E2F transcription factors was determined in four independent pediatric neuroblastoma cohorts from Therapeutically Applicable Research to Generate Effective Treatments (TARGET), Gene Expression Omnibus (GEO) and European ArrayExpres datasets using Kaplan–Meier and cox regression analysis. Results E2F regulated gene set was associated with the event free survival and the overall survival of neuroblastoma. E2F1 and E2F3 were prognostic factors in all four independent pediatric neuroblastoma cohorts. Over-expressions of E2F1 or E2F3 were correlated with the shorted event free survival and overall survival of neuroblastoma. Expression levels of E2F1 and E2F3 were higher in neuroblastoma patients with MYCN amplification or age at diagnosis ≥ 18 months. Moreover, the prognostic significance of E2F1 or E2F3 in neuroblastoma was independent of MYCN amplification and age of diagnosis. Combinations of E2F1 , E2F3 with MYCN amplification or age of diagnosis achieved better prognosis of neuroblastoma. Identification of 234 genes were associated with E2F1 and E2F3 expressions in neuroblastoma and those genes were significantly enriched in cell cycle signaling pathway. Also, higher scores of cell cycle signaling pathway were correlated with the adverse prognosis of neuroblastoma. Conclusions E2F transcription factors E2F1 and E2F3 were prognostic makers of neuroblastoma.

Background TP53 is rarely mutated in paediatric neuroblastoma. The prognosis of TP53 and TP53 -associated genes in paediatric neuroblastoma is unclear. The objectives of the study were to analyse datasets of 2477 paediatric neuroblastoma patients from eight independent cohorts to reveal the prognosis of TP53 and TP53 -associated genes. Results High TP53 mRNA expression was associated with shortened event-free survival and overall survival in paediatric neuroblastoma. Moreover, a higher enrichment score of the TP53 signalling pathway was associated with worse clinical outcomes of paediatric neuroblastoma. Among the genes associated with TP53 , CCNE1 , CDK2 and CHEK2 were correlated with unfavourable clinical outcomes, while SESN1 was correlated with favourable clinical outcomes of paediatric neuroblastoma in the eight independent neuroblastoma cohorts. TP53 , CCNE1 , CDK2 and CHEK2 were overexpressed in neuroblastoma patients with MYCN amplification, while SESN1 was downregulated in neuroblastoma patients with MYCN amplification. CCNE1 , SESN1 , MYCN amplification and age at diagnosis were independent prognostic markers of neuroblastoma. CCNE1 was also highly expressed in paediatric neuroblastoma patients with an age at diagnosis ≥ 18 months, while SESN1 was downregulated in paediatric neuroblastoma patients with an age at diagnosis ≥ 18 months. Combinations of CCNE1 with age at diagnosis or combinations of SESN1 with age at diagnosis achieved superior prognostic effects in paediatric neuroblastoma. Finally, we constructed a nomogram risk model of paediatric neuroblastoma based on age and TP53 , CCNE1 , CDK2 , CHEK2 and SESN1 expression. The nomogram model could predict the overall survival of paediatric neuroblastoma and MYCN nonamplified paediatric neuroblastoma with high specificity and sensitivity. Conclusions TP53 and TP53 -associated genes CCNE1 , CDK2 , CHEK2 and SESN1 were significantly associated with the clinical outcomes of paediatric neuroblastoma.