Khalaf N, Sandoval G, Zimolzak AJ
… +3 more, Kapadia P, Liu Y, Singh H
Br J Cancer
· 2026 Apr · PMID 41691061
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BACKGROUND: Over half of patients with pancreatic cancer experience an emergency cancer diagnosis, but tools for large-scale study are lacking. Towards this end, we developed a digital quality measure (dQM) to automate t...BACKGROUND: Over half of patients with pancreatic cancer experience an emergency cancer diagnosis, but tools for large-scale study are lacking. Towards this end, we developed a digital quality measure (dQM) to automate the detection of pancreatic cancer emergency presentations (EPs). METHODS: A dQM for pancreatic cancer EPs was developed within the U.S. Veterans Affairs health care system. Multivariable regression models were used to study the associations between EPs and cancer outcomes. Records of EP cases were manually reviewed to identify missed opportunities in diagnosis. RESULTS: The dQM had a positive predictive value of 86.4% (95% CI 80.0-92.8) for accurately identifying EPs among patients with pancreatic cancer. Among 4415 pancreatic cancer patients, 60.9% were identified as EPs by the measure. Patients with EPs had more advanced-stage disease (adjusted OR 1.38; 95% CI 1.20-1.59) and higher mortality (adjusted HR 1.64; 95% CI 1.51-1.77). Nearly one in five EP cases had missed opportunities in diagnosis. CONCLUSIONS: Our dQM had strong performance characteristics for identifying pancreatic cancer EPs, which were independently associated with worse patient outcomes. A notable subset of cases was potentially avoidable. The dQM is a promising strategy for health care systems to identify and measure EPs for quality improvement initiatives.
Montiel Equihua C, Molenaar JJ, Areso I
… +30 more, Biegel JA, Blanc P, Chi SN, Daems S, Danielson L, Drost J, Franke NE, Frühwald MC, Gajjar A, Geller JI, Huang A, Johann PD, Kearns P, Nysom K, O'Connor S, Ortiz MV, Parker J, Patel S, Patel S, Roberts CW, Williamson D, Yi JS, Pearson AD, Jenkinson D, Kool M, Bourdeaut F, LifeArc, Innovative Therapies for Children with Cancer (ITCC), Cancer Research UK, Cancer Grand Challenge PROTECT team
Br J Cancer
· 2026 Jun · PMID 41680284
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Rhabdoid tumours (RT) are malignancies of the central nervous system, kidneys, liver and soft tissues that most commonly affect very young children with survival rates below 30% in high-risk cohorts. Treatment entails su...Rhabdoid tumours (RT) are malignancies of the central nervous system, kidneys, liver and soft tissues that most commonly affect very young children with survival rates below 30% in high-risk cohorts. Treatment entails surgery, intensive chemotherapy and radiotherapy, associated with substantial short- and long-term toxicities. There is an unmet need to develop targeted therapies for RT to improve patient outcomes and mitigate the toxicities of current therapy. Detailed research followed by a workshop had the objective of enabling the development of targeted therapeutics for RT. Given the inherent commonality of their biology (i.e. biallelic inactivation of SMARCB1 or more rarely SMARCA4) the therapeutic approach should be similar for intra-cranial and extra-cranial tumours. DDB1-CUL4-associated factor 5 is a promising target, and the development of small molecule binders/degraders is a priority. Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) degraders may have greater therapeutic potential than inhibitors. Fibroblast growth factor receptor and platelet-derived growth factor receptor inhibitors may have value in subgroups. Mouse double minute 2 homologue (MDM2) is a priority target for novel therapeutic development and combination trials. Combinations of EZH2, MDM2 inhibitors and selective inhibitors of nuclear export should be evaluated robustly preclinically and drive early clinical studies.
Blanchet B, Puszkiel A, Jouinot A
… +17 more, Bennamoun M, Maillet D, Borchiellini D, Laguerre B, Pannier D, Gross-Goupil M, Chevreau C, Barthélémy P, Tournigand C, Coquan E, Gravis G, Lepicard E, Fridman WH, Sautes-Fridman C, Oudard S, Sun CM, Vano YA
Br J Cancer
· 2026 Apr · PMID 41652222
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BACKGROUND: We aimed to investigate the exposure-response (E/R) relationship for ipilimumab and nivolumab in metastatic clear cell renal cell carcinoma (m-ccRCC) patients from the randomised phase 2 BIONIKK trial (EudraC...BACKGROUND: We aimed to investigate the exposure-response (E/R) relationship for ipilimumab and nivolumab in metastatic clear cell renal cell carcinoma (m-ccRCC) patients from the randomised phase 2 BIONIKK trial (EudraCT 2016-003099-28). METHODS: This study included patients treated with either single-agent nivolumab (Nivo monotherapy group, n = 39) or nivolumab plus ipilimumab (Ipi/Nivo group, n = 71). Trough plasma concentrations (C) were assayed at week 6 after treatment start. Cox proportional hazard and logistic regression models were used to investigate the E/R relationship between C and clinical outcomes. RESULTS: Low nivolumab C (<median) was not identified as an independent risk factor for progression in either the Nivo monotherapy group (HR 2.03, 95% CI [0.93-4.44]; p = 0.076) or the Ipi/Nivo group (HR 1.06, 95% CI [0.63-1.79]; p = 0.83). Interestingly, low ipilimumab C (<4.9 µg/mL) was independently associated with worse PFS in the Ipi/Nivo group (HR 1.77, 95% CI [1.03-3.05]; p = 0.040). In both groups, neither nivolumab C nor ipilimumab C was associated with the risk of death or grade ≥ 3 TRAEs occurrence. CONCLUSIONS: This study suggests an E-R relationship for the efficacy of ipilimumab in m-ccRCC patients treated in combination with nivolumab. Prospective validation of our efficacy threshold in larger cohorts or phase 3 trials is essential prior to the implementation of a pharmacokinetically guided strategy.
Shaaban AE, Jourdain H, Desplas D
… +3 more, Vignot S, Zureik M, Haddy N
Br J Cancer
· 2026 Apr · PMID 41644812
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BACKGROUND: Sacituzumab govitecan (SG) was granted early access in France as third-line therapy for metastatic triple-negative breast cancer (mTNBC) and hormone receptor-positive/HER2-negative (HR+/HER2-mBC) metastatic b...BACKGROUND: Sacituzumab govitecan (SG) was granted early access in France as third-line therapy for metastatic triple-negative breast cancer (mTNBC) and hormone receptor-positive/HER2-negative (HR+/HER2-mBC) metastatic breast cancer. This nationwide cohort study assessed its real-world use and survival outcomes. METHODS: Using the French National Health Data System, we included all patients initiating SG between July 1, 2021, and December 31, 2023, with follow-up until June 30, 2024. Patient demographics, comorbidities, and prior treatments were recorded. Overall survival (OS) and time to treatment discontinuation (TTD) were estimated by Kaplan-Meier methods, and multivariable Cox models identified OS prognostic factors. RESULTS: 3653 patients were included: 2527 mTNBC and 1,126 HR+/HER2- mBC, with median ages of 58 and 61.5 years. Median OS was 11.0 months (95%CI: 10.4-11.7) for mTNBC and 11.4 months (95% CI: 10.7-12.4) for HR+/HER2-mBC. One-year survival was 47% and 48% and median TTD of 4.3 and 3.5 months, respectively. Poorer OS was independently associated with inpatient SG initiation and liver/digestive metastases. In mTNBC, additional factors included brain metastases, respiratory disease, tobacco-related hospitalisation, multiple metastatic sites, and prior treatments. CONCLUSION: The study highlights SG's clinical relevance and the challenge of translating trial efficacy into real-world outcomes, reinforcing the need for further investigation of tolerability in broader populations.
Martin J, Jones DA, Ellis L
… +6 more, Gray E, Halliday K, Hiom S, McPhail S, Millar A, Hamilton W
Br J Cancer
· 2026 Apr · PMID 41620498
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BACKGROUND: People with a cancer signal detected via multi-cancer early detection (MCED) screening need timely access to confirmatory diagnostic testing. We estimated the likely change in demand for diagnostic testing in...BACKGROUND: People with a cancer signal detected via multi-cancer early detection (MCED) screening need timely access to confirmatory diagnostic testing. We estimated the likely change in demand for diagnostic testing in England if MCED screening were introduced. METHODS: Diagnostic demand was modelled based on (1) estimates of the volume of people aged 50-79 years who would be referred for diagnostic investigation following a 'cancer signal detected' result after MCED screening and (2) MCED test performance metrics. Predicted usage was compared with current annual usage using routine NHS datasets. RESULTS: In an established MCED screening programme, assuming 70% of the total eligible population is screened annually (~13 million), the relative change in diagnostic demand was greatest for colonoscopy (+2.09%; +13,730 each year); the greatest absolute change was for computed tomography (CT; +0.76%; +62,320). This equates to +1040 colonoscopies and +4720 CT scans for every million screened. CONCLUSIONS: The predicted relative increase in diagnostic testing generated by MCED screening is small, though a large eligible population and maximum uptake could translate into a large number of procedures. Cancer diagnoses brought forward in time through screening should reduce diagnostic use for symptomatic presentations in the future.
Li J, Jiang W, Tu G
… +4 more, Zhong Z, Luo Z, Horng T, Miao C
Br J Cancer
· 2026 Apr · PMID 41611989
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BACKGROUND: Fasting-mimicking diet (FMD) is a safe and effective strategy in clinical oncology via metabolically restricting tumour growth and remodelling the immunity. To date, few studies have investigated the impact o...BACKGROUND: Fasting-mimicking diet (FMD) is a safe and effective strategy in clinical oncology via metabolically restricting tumour growth and remodelling the immunity. To date, few studies have investigated the impact of on tumour-associated macrophages (TAMs), which are a crucial component of immune cells in the tumour microenvironment. Fasting can induce the ubiquitin-proteasome system (UPS) to regulate intracellular protein turnover homoeostasis, while Nuclear Factor Erythroid 2-like 1 (NRF1; encoded by the gene Nfe2l1), which controls proteasome gene transcription, may potentially be induced by fasting. However, whether NRF1 is induced by FMD/fasting, and how NRF1-mediated protein turnover works on TAMs remain unknown. This study investigated the hypothesis that FMD activates the anti-tumour immunity of TAMs by ubiquitinated protein metabolism. METHODS: Subcutaneous MC38 tumour models were established in WT and myeloid-specific NRF1 knockout (Mye-NFE2L1) C57BL/6 mice, treated with FMD alone or combined with intraperitoneal Trex1 inhibitor (Trex1-IN-1). TAMs were isolated from tumour tissues using CD11b magnetic bead sorting. In vitro, bone marrow-derived macrophages (BMDMs) were co-cultured with MC38 in fasting medium, with MC38 proliferation assessed by CCK8 assay. BMDM-derived TAMs (B-TAMs) were induced by MC38 supernatant under fasting conditions. IFNβ levels in serum and cell supernatant were measured by ELISA. RNA-seq was performed to compare WT and Mye-NFE2L1 BMDMs under fasting conditions. Protein levels of cGAS-Sting pathway components, ubiquitinated proteins, and nuclear NRF1 were analysed by Western blot, while Trex1 ubiquitination was assessed by Co-IP. qPCR quantified IFNβ-related gene expression and mitochondrial DNA (mtDNA) copy number. Trex1-mitochondria colocalization was examined by immunofluorescence, and Trex1-bound mtDNA levels were determined by ChIP-qPCR. RESULTS: FMD/fasting triggers interferon-β (IFNβ) secretion in TAMs, which is driven by protein metabolism. In TAMs with FMD, an initial accumulation of ubiquitinated proteins occurs concomitantly with the induction of NRF1 in response to fasting-induced energy stress, leading to the ubiquitin/proteasome-dependent proteolysis of the three prime repair exonuclease 1 (Trex1) through UPS. Such a process engages type I interferon responses, which derepress the cGAS-Sting-IFNβ axis to promote anti-tumour effects of TAMs. In the absence of NRF1, Trex1 accumulates due to impaired UPS and binds to mtDNA, disrupting cGAS sensing of mtDNA to inhibit IFNβ secretion in TAMs, which attenuates anti-tumour effects of FMD/fasting. CONCLUSION: In this study, we revealed for the first time that FMD/fasting coordinates NRF1-UPS and Trex1/Sting-mediated type I interferon responses in TAMs that contribute to suppressing tumour growth. Graphical abstract: FMD upregulates the entry of NRF1 into the TAM nucleus to promote gene expression of proteasome subunits, which induces the ubiquitin/proteasome-dependent proteolysis of Trex1, leading to derepression of the cGAS-Sting-IFNβ axis. On the other hand, FMD triggers increasing of mtDNA in TAMs, promoting the cGAS-Sting-IFNβ axis to release IFNβ. In myeloid NRF1 knockout TAMs, transcriptional levels of proteasome subunits are reduced, resulting in impaired proteolysis of Trex1 and its subsequent accumulation during fasting. Then, Trex1 binds to mtDNA, directing the inhibition of the cGAS-Sting-IFNβ axis and inhibiting IFNβ secretion of macrophages.
Luo Y, Peng H, Yao Q
… +8 more, Xie Y, Liu D, Wang Y, Peng Z, Shen L, Sun Y, Zhang X, Chen Y
Br J Cancer
· 2026 Apr · PMID 41588173
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BACKGROUND: V-domain Ig-containing suppressor of T cell activation (VISTA) is an immune checkpoint molecule predominantly expressed on myeloid cells and has recently been recognised as a key mediator of immunosuppression...BACKGROUND: V-domain Ig-containing suppressor of T cell activation (VISTA) is an immune checkpoint molecule predominantly expressed on myeloid cells and has recently been recognised as a key mediator of immunosuppression within the tumour microenvironment (TME). However, its expression pattern in gastric cancer and the functional characteristics of the VISTA-high TME remain poorly understood. METHODS: We conducted multiplex immunohistochemistry on tumour samples from 172 patients to characterise the immune landscape of the VISTA-high tumour microenvironment. Additionally, single-cell RNA sequencing (n = 17) and spatial transcriptomics (n = 3) were employed to delineate the cellular expression patterns of VISTA and investigate the potential immunomodulatory functions of VISTA-expressing macrophages. RESULTS: High VISTA expression was associated with an immunosuppressive TME characterised by increased infiltration of exhausted CD8 T cells, regulatory T cells (Tregs), M2-like macrophages, and cancer-associated fibroblasts (CAFs). Moreover, elevated VISTA levels in the tumour region were linked to worse immune-related progression-free survival (irPFS) in patients treated with immune checkpoint inhibitors (ICIs). Mechanistically, VISTA monocyte-macrophage (MoMac) populations promoted T cell exhaustion via the LGALS9-PTPRC signalling axis and exhibited enhanced antigen-presenting capacity. CONCLUSIONS: Our findings establish VISTA as a central immunoregulatory checkpoint in gastric cancer, suggesting its potential as a promising therapeutic target for combination immunotherapeutic approaches.
Horcicka A, Bewersdorf N, Kalkum E
… +6 more, Zimmermann S, Grüßer L, Dehne S, Weigand MA, Klotz R, Larmann J
Br J Cancer
· 2026 Apr · PMID 41548030
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BACKGROUND: Patients undergoing gastrointestinal cancer surgery are often immunocompromised and susceptible to infectious complications. Recombinant Interleukin 2 activates effector immune cells and stimulates the expans...BACKGROUND: Patients undergoing gastrointestinal cancer surgery are often immunocompromised and susceptible to infectious complications. Recombinant Interleukin 2 activates effector immune cells and stimulates the expansion of regulatory T-cells, making it a promising intervention for prevention of inflammatory complications. OBJECTIVE: Our objective was to investigate effects of different preoperative rIL2 dosages on postoperative outcome parameters. METHODS: We conducted a systematic literature review and meta-analysis and included RCTs that recruited adult patients undergoing gastrointestinal cancer surgery who received preoperative subcutaneous rIL2. We performed a systematic search of MEDLINE (via PubMed), Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL) from 1989 up to April 18th, 2024. RESULTS: Out of 2324 screened studies, we included 13 RCTs with a total of 504 patients. Lymphocyte counts [cells/mm] at 1 week postoperative were higher in the intervention compared to the control group (MD 865 (95%CI: 26, 1705)). Surgical site infections and systemic infections were less likely to occur in the intervention group (OR 0.13 (95%CI: 0.03, 0.50); OR 0.25 (95%CI: 0.10, 0.66)). Severe side effects of rIL2 were not reported. CONCLUSION: Preoperative rIL2-based immunomodulation prevents postoperative immunosuppression while the occurrence of severe side effects does not seem to be relevant.
Shi DB, Qin YC, Liu S
… +4 more, Zhao RN, He JY, Ma RR, Gao P
Br J Cancer
· 2026 Apr · PMID 41540191
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BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors with poor overall survival (OS). The mechanism underlying the progression of GC needs to be investigated in depth. METHODS: Differentially expres...BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors with poor overall survival (OS). The mechanism underlying the progression of GC needs to be investigated in depth. METHODS: Differentially expressed genes (DEGs) were identified based on The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma (STAD) and Gene Expression Omnibus (GEO) datasets in GC. The function of INHBA in GC was investigated in vitro and in vivo. Dual-luciferase reporter, chromatin immunoprecipitation (ChIP), and western blot assays were performed to identify the target transcription factors. Immune cell infiltration was assessed using CIBERSORT algorithms. M2 macrophage polarization induced by INHBA was detected in vitro. The expression levels of downstream target genes of INHBA were measured at mRNA and protein levels. RESULTS: INHBA was upregulated in GC cells, and high expression of INHBA was associated with poor OS. INHBA was able to promote GC cell migration, invasion, and tumor metastasis and growth. INHBA expression was upregulated by the transcription factor C/EBPβ. Moreover, INHBA in GC cells mediated M2 macrophage polarization. Of note, our data showed that INHBA activated PI3K/AKT pathway and formed a PI3K/AKT/TGF-β positive feedback loop to promote tumor progression. CONCLUSIONS: High INHBA expression predicts poor survival of GC patients. INHBA, upregulated by C/EBPβ, induces M2 macrophage polarization to promote tumor metastasis and growth via activating PI3K/AKT pathway in GC. INHBA may be a potential therapeutic target for GC.
Martin S, Elomaa H, Väyrynen JP
… +14 more, Ahtiainen M, Wirta EV, Böhm J, Seppälä TT, Ristimäki A, Tahkola K, Mattila A, Koskensalo S, Renkonen-Sinisalo L, Lepistö A, Mecklin JP, Palin K, Rajamäki K, Aaltonen LA
Br J Cancer
· 2026 Apr · PMID 41535448
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BACKGROUND: The high mutational burden in microsatellite unstable colorectal cancers (MSI CRCs) results in high immunogenicity, yet response rates to immunotherapy vary, suggesting underlying heterogeneity of the tumour...BACKGROUND: The high mutational burden in microsatellite unstable colorectal cancers (MSI CRCs) results in high immunogenicity, yet response rates to immunotherapy vary, suggesting underlying heterogeneity of the tumour immune landscape. Here, our aims were (1) to characterise the immune cell infiltrate and immune evasion in MSI CRCs, (2) to correlate these with clinical and genomic features, and (3) to compare these between Lynch syndrome (LS) and sporadic MSI CRCs. METHOD: Immunohistochemistry was utilised to detect T cell and myeloid cell subsets. Whole-genome and RNA sequencing were utilised to analyse somatic variants, tumour clonality, neoantigen burden, antigen presentation, immune checkpoint expression, and consensus molecular subtypes. RESULTS: Our results revealed higher immune cell scores in LS tumours, depicting higher T cell infiltration, compared to sporadic tumours. Conversely, sporadic tumours displayed increased infiltration of protumorigenic M2-like macrophages and increased expression of immune checkpoints PDCD1LG2 and CD40LG. Across our MSI CRC cohort, high neoantigen burden was associated with low tumour clonality. CONCLUSIONS: Our findings reveal differences between sporadic MSI and LS tumours in T cell and myeloid immune cell landscapes, and in immune evasion. These differences may contribute to the variable immunotherapy responses among MSI CRC patients and are targetable by emerging therapeutic approaches.
Ball M, Beck S, Wlochowitz D
… +23 more, Fuchs T, Lorenz K, Zgorzelski C, Pallares Robles A, Allgäuer M, Volckmar AL, Goldschmid H, Ourailidis I, Brandt R, Christopoulos P, Thomas M, Seker-Cin H, Fink A, Schnecko F, Neumann O, Menzel M, Kirchner M, Fioretos T, Schirmacher P, Peters S, Budczies J, Stenzinger A, Kazdal D
Br J Cancer
· 2026 Apr · PMID 41530577
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BACKGROUND: Whole Transcriptome Sequencing (WTS) is a comprehensive alternative to targeted panels for detecting gene fusions and splice variants. To integrate WTS into clinical diagnostics, we compared its performance a...BACKGROUND: Whole Transcriptome Sequencing (WTS) is a comprehensive alternative to targeted panels for detecting gene fusions and splice variants. To integrate WTS into clinical diagnostics, we compared its performance against established fusion assays (Archer FusionPlex and TSO500 RNA). METHODS: WTS was evaluated in an initial cohort of 64 FFPE tumor samples, and quality control (QC) thresholds were defined based on missed fusions correlating with low tumor cell content (TCC < 40%). Key QC metrics included TCC ≥ 40%, RNA input ≥50 ng, ≥50 million reads, and median insert size >100 bp. RESULTS: WTS identified 92% of known fusions in the initial cohort. Validation in 357 samples showed 100% concordance with panel-based results when QC thresholds were met. Subsequent clinical deployment across 812 diverse tumor cases detected 121 fusions, though 423 (34%) required fallback to targeted assays due to low TCC. WTS provided added value by detecting novel fusions, pathogens, and enabling oncogenic pathway analysis. CONCLUSION: WTS is a reliable and informative method for fusion and splice variant detection in clinical diagnostics, provided rigorous pre-analytical and sequencing QC metrics are strictly applied.
Praud D, Amadou A, Mercoeur B
… +14 more, Duboeuf M, Bouilly M, Coudon T, Grassot L, Faure E, Couvidat F, Caudeville J, Bessagnet B, Salizzoni P, Leffondré K, Gulliver J, Severi G, Mancini FR, Fervers B
Br J Cancer
· 2026 Apr · PMID 41530576
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BACKGROUND: Airborne particulate matter (PM) is a complex mixture of particles thought to be associated with a range of adverse health effects, including female breast cancer. Current evidence on the association between...BACKGROUND: Airborne particulate matter (PM) is a complex mixture of particles thought to be associated with a range of adverse health effects, including female breast cancer. Current evidence on the association between PM and female breast cancer risk is inconsistent. METHODS: This study investigated the association between long-term exposure to PM and breast cancer risk in a nested case-control study within the French E3N-Generation cohort including 5222 breast cancer cases identified over the 1990-2011 follow-up period and 5222 individually matched controls. Annual mean concentrations of PM and PM at participants' residential addresses, were estimated using a land use regression model. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression models. RESULTS: ORs for each 10 µg/m increase in the average of PM and PM were 1.14 (95% CI: 0.99-1.30) and 1.08 (95% CI: 0.98-1.18), respectively. When restricted to invasive ductal and lobular carcinomas, ORs were 2.74 (95% CI: 1.05-7.15) for PM and 2.05 (95% CI: 1.11-3.78) for PM. Comparable effects of PM exposure estimated by a chemistry transport model reinforces these findings. CONCLUSION: This study suggests a potential association between PM and PM exposure and breast cancer risk.
Rong Z, Xing J, Wu L
… +4 more, Zheng K, Pang L, Chen J, Jin X
Br J Cancer
· 2026 Apr · PMID 41530575
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BACKGROUND: Oxaliplatin resistance continues to undermine therapeutic outcomes in colon cancer (CC). Recent investigations point to unc-51 like kinase 1 (ULK1)-mediated disruption of apoptotic pathways as a potential dri...BACKGROUND: Oxaliplatin resistance continues to undermine therapeutic outcomes in colon cancer (CC). Recent investigations point to unc-51 like kinase 1 (ULK1)-mediated disruption of apoptotic pathways as a potential driver of chemoresistance, though the exact mechanisms remain incompletely characterized. METHODS: Using established CC cell lines, we developed oxaliplatin-resistant models through stepwise dose escalation. ULK1 expression was modulated through targeted siRNA knockdown and stable overexpression. Protein interactions were examined via co-immunoprecipitation coupled with mass spectrometry, supplemented by kinase activity assays. Functional impact was assessed through proliferation kinetics, apoptosis profiling, and tumor xenograft studies. Clinical correlations were derived from TCGA analysis and immunohistochemical evaluation of patient tumor specimens. RESULTS: ULK1 overexpression consistently correlated with oxaliplatin resistance and adverse clinical parameters. At the molecular level, ULK1 catalyzed Bcl-2 associated X protein (Bax) phosphorylation at Ser184, creating a recognition motif for Parkin-mediated ubiquitination and proteasomal targeting. Disruption of this axis through ULK1 inhibition restored Bax protein levels, enhanced apoptotic response, and reversed oxaliplatin resistance in both cellular and animal models. CONCLUSION: These findings identify ULK1-dependent phosphorylation as a novel regulatory mechanism governing Bax stability in CC. The study provides preclinical rationale for targeting the ULK1-Bax interface to overcome oxaliplatin resistance, while highlighting the need for further investigation into optimal therapeutic strategies.
Stoop TF, Wu YHA, Oba A
… +7 more, Ali M, Messersmith W, Besselink MG, Burkhart RA, Wilmink JW, Del Chiaro M, International Consortium on Pancreatic Cancer Surgery and Oncology (ICON)
Br J Cancer
· 2026 Feb · PMID 41526658
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Herrero Colomina J, Hu X, Dinizulu H
… +5 more, Yan R, Poles E, Dawson R, Yap C, Carter L
Br J Cancer
· 2026 Apr · PMID 41520059
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The urgent need for drug development for cancer patients and the complexity of novel therapies have led to the increasing importance of expansion cohorts (EC) within phase 1 trial design. We conducted a systematic review...The urgent need for drug development for cancer patients and the complexity of novel therapies have led to the increasing importance of expansion cohorts (EC) within phase 1 trial design. We conducted a systematic review of oncology phase 1 trials with EC published from 2019 to 2023. The objective was to assess the characteristics, purpose and outcomes of EC. A mixed-effects meta-regression model was conducted to analyse response rates. 479 published phase 1 trials with EC were included (median number of EC patients per trial: 27). The EC objective was stated in 55.7% of studies (76.8% safety, 16.5% dosing, 25.8% pharmacokinetics, 22.1% pharmacodynamics, 77.5% preliminary efficacy). 117 trials (24.4%) included a statistical justification plan. The mean Overall Response Rate (ORR) was 20.2% in solid tumours and 46.8% in haematological malignancies. Among drug classes, Antibody-drug conjugates showed the highest ORR (32.1%). Higher ORR was significantly associated with combination therapies, haematological trials, trials with statistical justification for EC sample size and trials not containing Immunotherapy. EC have evolved to become large dynamic studies assessing both preliminary efficacy and safety. This study highlights the importance of clearly stated EC objectives and sample size justification to enhance the rigour and interpretability of early-phase evidence.
Br J Cancer
· 2026 Apr · PMID 41520058
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BACKGROUND: Metabolomic dysregulation contributes to prostate cancer (PCa) pathogenesis, and studies suggest that circulating metabolites have strong potential to act as clinical biomarkers. However, evidence of associat...BACKGROUND: Metabolomic dysregulation contributes to prostate cancer (PCa) pathogenesis, and studies suggest that circulating metabolites have strong potential to act as clinical biomarkers. However, evidence of associations between circulating metabolites with overall and clinically significant PCa risk has not been quantitively aggregated. METHODS: We performed a systematic review and meta-analysis of untargeted pre-diagnostic circulating metabolomic studies across four clinically distinct outcomes: overall, low- to intermediate-risk, high- to very high-risk, and lethal PCa, each compared to controls. RESULTS: Twelve studies were identified in the systematic review, and up to 408 metabolites were meta-analysed across the four PCa outcomes. Three, eleven, and nineteen metabolites were significantly associated with risk of overall, high- to very high-risk, and lethal PCa, respectively. Metabolites associated with high- to very high-risk PCa were significantly enriched for lipids. Limited evidence of correlation between metabolite effects across outcomes was identified, highlighting potentially unique metabolite drivers of high-risk and lethal PCa. In follow-up analyses, 13 of the significant metabolites were found to be modifiable by drugs and/or diet. CONCLUSIONS: These findings suggest a strong potential for metabolites to inform risk of lethal PCa, which could inform risk-stratified screening strategies and facilitate the identification of targets for PCa prevention.
Dong Z, Xie W, Zhang N
… +5 more, Guo Y, Zhang Y, Liu Y, Lin C, Shao F
Br J Cancer
· 2026 Mar · PMID 41520057
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BACKGROUND: Despite significant advances in diagnosis and therapy, the prognosis of late-stage lung adenocarcinoma (LUAD) remains poor, underscoring the urgent need for effective biomarkers to enable early detection. Epi...BACKGROUND: Despite significant advances in diagnosis and therapy, the prognosis of late-stage lung adenocarcinoma (LUAD) remains poor, underscoring the urgent need for effective biomarkers to enable early detection. Epigenetic alterations, particularly DNA methylation, is essential for controlling gene expression, and its abnormality plays critical roles in promoting carcinogenesis. METHODS: Reduced representation bisulfite sequencing (RRBS) technique was used to establish the DNA methylation profile in early-stage LUAD in comparison to normal tissues. The epigenetic abnormalities and expression, as well as the functions of ArfGAP with coiled-coil, ankyrin repeat and PH domains 3 (ACAP3) in LUAD carcinogenesis were further investigated. RESULTS: we investigated the DNA methylation dysregulation during tumorigenesis in the early-stage LUAD, and identified that Myc-mediated DNA hypermethylation and deacetylation as key mechanisms suppressing ACAP3 expression. ACAP3 significantly suppresses the proliferation of LUAD cells in vitro and in vivo. Mechanically, ACAP3 inhibits epidermal growth factor receptor (EGFR) signalling via impairing EGFR recycling and accelerating lysosome-mediated EGFR degradation in a GTPase-activating protein (GAP) activity-dependent manner. CONCLUSION: Our finding reveals that ACAP3, suppressed by Myc-mediated epigenetic abnormality in early-stage LUAD, acts as a tumour suppressor by inhibiting EGFR signalling and cells proliferation, suggesting its potential as a diagnostic and therapeutic target.