Pancreatic cancer is a major cause of death and one of the most challenging types of cancer which responds poorly to conventional chemotherapy and has limited therapeutic options. The scenario highlights the urgent need for the development of newer multi-targeting anticancer drugs for pancreatic cancers with higher potency, selectivity and safety profiles. The proposed research was focused on revealing the anticancer potential and mechanistic involvement of naturally occurring sesquiterpenoid nootkatone against pancreatic cancer through an integrative in silico approach. Network pharmacology and systems biology approaches were applied to identify common therapeutic targets for nootkatone that were pathophysiologically associated with the progression of pancreatic cancer. Protein-protein interaction (PPI), Gene Ontology (GO), and KEGG enrichment analyses were executed to validate the target's involvement in the pathophysiology of pancreatic cancer. Molecular docking and dynamics simulations were performed to reveal the binding potential and interactions of the nootkatone with the shortlisted anticancer targets, followed by density functional theory (DFT) analysis, ADMET prediction, and clinical relevance assessment to confirm its electrochemical and physicochemical involvement. A total of 27 overlapping targets were identified with AKT1, MAPK3, IL1β, and COX-2 revealed as the four hub target genes for nootkatone by network pharmacology. Enrichment analyses confirmed the significant involvement of PD-L1/PD-1 immune checkpoint, PI3K-AKT, MAPK, and inflammatory signaling pathways (FDR < 0.05) in the progression of pancreatic cancer. Docking analyses revealed that nootkatone has binding affinity for its targets, especially for MAPK3/ERK1 (- 8.03 kcal/mol) and AKT1 (- 7.35 kcal/mol). MD simulation over 100 ns demonstrated the stable protein-ligand complexes. DFT calculations showed a HOMO-LUMO energy gap of 2.868 eV, indicating moderate chemical reactivity and stability. Nootkatone was found to exert stronger and more stable binding against all four concerned anticancer targets with impressive electrochemical properties. ADMET predictions suggested favourable drug-likeness and Pharmacokinetics. Nootkatone can be a potential multi-targeting agent with anticancer and immunomodulatory properties by modulating the PD-L1/PD-1 immune checkpoint and signalling pathways associated with pancreatic cancer progression. However, these findings are based on in silico analyses and require further validation through in vitro and in vivo experimental studies to develop new plant-based anticancer therapeutics for pancreatic cancer.
Post-translational modifications (PTMs) are crucial regulatory mechanisms that modulate the structure, function, and stability of proteins, playing an essential role in the regulation of cellular processes. Dysregulated PTMs are associated with various aspects of cancer development, including uncontrolled cell growth, evasion of apoptosis, metastasis, and drug resistance. This review offers a detailed examination of several major PTMs, including phosphorylation, acetylation, ubiquitination, SUMOylation, and methylation, discussing their distinct roles in cancer biology. It also provides an in-depth analysis of the latest advancements in the study of PTMs in cancer biology, focusing on the mechanisms by which these modifications contribute to tumorigenesis and their potential as therapeutic targets. It highlights the significant progress made in the identification of PTMs across different cancer types, emphasizing the role of PTMs in shaping cancer progression and immune modulation. Additionally, the paper discusses cutting-edge technologies, particularly mass spectrometry and computational proteomics, that have revolutionized the detection and characterization of PTMs. These advancements have enabled the identification of novel cancer biomarkers and therapeutic targets, offering new avenues for early detection, prognostic monitoring, and the development of targeted therapies in cancer treatment.
Chemotherapy-induced alopecia (CIA) remains one of the most distressing adverse effects of cancer therapy. Yet, no therapy is available to selectively protect healthy hair follicles (HFs) and their epithelial stem cells (eHFSCs) from chemotherapy-induced damage without awarding potential survival benefits to cancer cells. Here, we report how human HFs can be protected against 2 lead CIA-inducing chemotherapeutics by inducing selective transient cell cycle arrest. Pretreating scalp HFs before chemotherapy exposure ex vivo with ALRN-6924, a clinical-stage "stapled peptide" drug that binds with high affinity to key endogenous inhibitors of p53, selectively activated p53 signaling only in cells with wild-type TP53 genotype and upregulated p21. This led to temporary cell cycle arrest in healthy tissues without protecting TP53-mutant cancer cells and mitigated chemotherapy-induced HF damage on multiple levels, including excessive hair matrix apoptosis, premature catagen, pigmentary abnormalities, "mitotic catastrophe," and micronucleation. It also protected eHFSCs against DNA damage, apoptosis, and pathological epithelial-mesenchymal transition. Notably, even topically applied ALRN-6924 afforded relative chemotherapy protection ex vivo. These results provide proof of principle for a strategy to selectively protect rapidly proliferating healthy epithelial tissues and their stem cells in patients with TP53-mutant cancers, which promises to protect against acute and permanent CIA.
Triple Negative Breast Cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), which is associated with a very poor prognosis. It is a broad category of tumors with a variety of biological, clinical, and morphological characteristics. FOXM1 is a pivotal transcription factor that modulates proliferation-associated genes through complex protein-DNA and protein-protein interactions, making it a highly attractive target in cancer therapy. However, existing small-molecule inhibitors often suffer from limited specificity and efficacy. In this study, we designed, synthesized, and evaluated novel series of 2-aminothiazole derivatives (C1-C15) as potential FOXM1 inhibitors. Molecular docking and molecular dynamics (MD) simulations were employed to investigate the binding interactions of these compounds with the FOXM1 DNA-binding domain (FOXM1-DBD). Structural analysis highlighted the importance of crucial residues, including Asn283, His287, and Arg286, in mediating inhibitory activity. Among the synthesized compounds, C11 exhibited remarkable structural alignment and interaction patterns with FOXM1-DBD, comparable to the reference inhibitor FDI-6. In vitro studies using TNBC cell lines (MDA-MB-231, BT-549, and BT-20) demonstrated that compound C11 significantly outperformed FDI-6 in potency. Western blot analysis revealed that C11 effectively suppressed FOXM1 transcriptional activity at concentrations of 10 µM in BT-549 cells and 20 µM in MDA-MB-231 cells. These findings underscore the potential of C11 as a potent FOXM1 inhibitor and highlight its promise for further development in TNBC therapy.
Cancer therapy-related cardiac dysfunction (CTRCD) has become an important clinical issue with advances in cancer treatment and improved patient survival. The Japanese Society of Echocardiography previously published practice guidance in 2020. The present document provides an updated revision reflecting recent developments in cardio-oncology. This guidance was developed based on contemporary evidence, including the 2022 European Society of Cardiology cardio-oncology guidelines, recent clinical studies, and advances in echocardiographic and multimodality imaging technologies. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) are emphasized as essential parameters for diagnosing and monitoring CTRCD. The document provides standardized protocols for echocardiographic evaluation before, during, and after cancer drug therapy, as well as recommendations for long-term surveillance following radiotherapy. It also addresses cardiovascular complications associated with immune checkpoint inhibitors, particularly myocarditis, and highlights the importance of measurement accuracy, quality control, artificial intelligence, and three-dimensional echocardiography in clinical practice. This updated guidance offers practical and evidence-based recommendations for echocardiographic assessment in cardio-oncology, aiming to facilitate early detection of cardiotoxicity and optimize multidisciplinary management.
Positron Emission Tomography (PET) has evolved from a purely diagnostic modality into a cornerstone of precision radiation oncology. PET now informs patient selection, target delineation, treatment personalization, and post-therapy evaluation across External Beam Radiation Therapy (EBRT) and Radiopharmaceutical Therapy (RPT). Radiotracers provide quantitative data on tumor biology, heterogeneity, receptor expression, and therapeutic response, enabling a shift from morphology-based to biology-driven oncology. PET-guided therapy is increasingly used to select patients for molecular radiotherapy, guide EBRT boost volumes, monitor receptor occupancy, and personalize activity prescription. Combined modality approaches-such as EBRT plus PSMA-RLT in prostate cancer or EBRT plus SSTR-RLT in neuroendocrine tumors-are supported by biological rationales involving synergy between external and internal radiation sources. Adaptive strategies based on mid-treatment PET show promise in improving local control while minimizing toxicity. This review summarizes the current landscape and emerging applications of PET-guided therapy, highlighting methodological synergies between EBRT and RPT, strategies for treatment sequencing, biological dose painting, and adaptive therapy. It provides practical recommendations for implementing PET-guided workflows and discusses advances in radiobiology-informed dosimetry, whole-body PET technologies, and novel imaging biomarkers, including fibroblast activation protein inhibitors (FAPI), as key drivers of innovation. As PET technology evolves toward ultra-low-dose, ultra-fast total-body systems, the role of molecular imaging in therapeutic decision-making is expected to expand, ushering in a new era of biologically guided radiation oncology.
The clinical translation of prostate-specific membrane antigen (PSMA)-directed chimeric antigen receptor (CAR) T-cell therapy for metastatic castration-resistant prostate cancer (mCRPC) has reached a critical impasse. Despite compelling preclinical rationale and early biological activity, durable clinical responses remain scarce, constrained by three core solid tumor challenges: a profoundly immunosuppressive/metabolically hostile tumor microenvironment (TME), pervasive antigen heterogeneity driving immune escape, and intrinsic limitations in T-cell fitness and in vivo persistence. This review synthesizes the current translational landscape (updated to February 2026), and posits a tripartite synergistic framework to systematically deconstruct these barriers: (1) advances in CAR synthetic biology; (2) active TME reprogramming via armored CAR-T cells, stromal-targeting agents, and rational combinations; (3) next-generation cellular product paradigms, with a focus on stem cell-derived immune effectors. Emerging platforms, including induced pluripotent stem cell (iPSC)-derived CAR-T, CAR-natural killer (NK) cells, and CAR-macrophages, offer unprecedented opportunities to overcome autologous product limitations via off-the-shelf availability, enhanced persistence, and intrinsic TME resistance. We further delineate a translational roadmap emphasizing biomarker-driven adaptive trials, predictive humanized preclinical models, and accessibility strategies. All core claims are graded using the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence to ensure academic rigor. This work provides a strategic blueprint to advance PSMA-CAR-T therapy toward curative-intent mCRPC treatment, with insights broadly applicable to next-generation stem cell-derived immunotherapies.
In the current study, an optimum formulation of alginate-functionalized and PEGylated niosomes (Nio) co-encapsulated with letrozole (Let) and berberine (Ber) was observed for potential preclinical treatment of breast cancer to combat multidrug resistance and reduce drug doses. The incorporation of alginate (AL) and polyethylene glycol (PEG) enabled tunable network architecture, improved colloidal stability, and sustained release behavior of the formulated system. Nio-Let/Ber@PEG and Nio-Let/Ber@AL formulations showed desired entrapment efficiencies of 86.12 and 91.34 for Let and 71.32 and 75.12 for Ber, respectively. Drug release profiles showed that sustained and slower release rates were observed for coated niosomes (Nio-Let/Ber@PEG and Nio-Let/Ber@AL) compared to uncoated niosomes (Nio-Let/Ber). MTT assay showed the IC50 of coated niosomes was much lower than the uncoated formulation and free drugs for MCF-7 and MDA-MB-231 breast cancer cell lines. Moreover, coated niosomal formulations significantly increased the rate of apoptosis induction and cell cycle arrest compared to uncoated niosomes. Also, gene expressions of Bax and caspase 3/8/9 increased while the gene expression of Bcl2 (anti-apoptotic) decreased after treatment with coated niosomes compared to uncoated ones. Taken together, this preliminary research indicated that the co-delivery of Let and Ber through coated niosomal formulations (Nio-Let/Ber@PEG and Nio-Let/Ber@AL) was an efficient controlled dual-drug delivery system to increase the effectiveness of breast cancer therapy.
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and one of the best-characterized drivers is oncogenic Wnt signaling. In this study, we demonstrated that Orlistat, an FDA-approved anti-obesity drug, is a unique inhibitor of oncogenic Wnt signaling and CRC. We confirmed that the known target FASN was not associated with Orlistat inhibition of CRC, and identified the NEDD8-conjugating enzyme UBC12 (UBE2M) as a candidate target instead. The direct engagement of Orlistat and UBC12 was confirmed by ITC assay with a KD value of 678nM. Of note, Orlistat inhibited the NEDD8-conjugating activity of UBC12 and blocked UBC12 interaction with DCN1 (defective in cullin neddylation 1), thereby selectively suppressing Cullin 1 neddylation. In addition, overexpression of UBC12 positively regulated Wnt/β-catenin signaling in normal cells, while depletion of UBC12 not only inhibited oncogenic Wnt signaling but also abrogated Orlistat's inhibition of Wnt signaling and cell proliferation in CRC cells. Taken together, our findings revealed UBC12 as a novel Orlistat target, and identified UBC12 as a potential therapeutic target for Wnt-dependent cancers.
Regulatory T cells (Tregs) form a distinct subset of CD4+ T cells essential for maintaining immune balance and preventing autoimmunity by expressing CD25 and CTLA-4. Tregs, which are defined by the expression of the transcription factor FOXP3 in mice, restrain excessive immune activation through mechanisms such as IL-10 expression, TGF-β expression, metabolic regulation, acting as an IL-2 cytokine sink, and cell-to-cell interaction through co-inhibitory receptors. Although they are indispensable for immune tolerance, Tregs can be co-opted by tumors, where their suppressive activity promotes immune escape. High Treg infiltration within the tumor microenvironment has been linked to variable prognosis depending on the tumor type, highlighting Tregs' contradictory roles as both guardians of tolerance and enablers of tumor progression. In this review, we summarize Treg biology, Tregs' contribution to cancer immunity, and emerging therapeutic strategies designed to modulate or deplete Tregs. We conducted a targeted literature review using PubMed/MEDLINE, Web of Science, ClinicalTrials.gov, and ASCO/ESMO meeting libraries, complemented by manual reference screening. We also discuss the limitations of existing therapeutic approaches and outline future directions. Efforts to therapeutically modulate Tregs have focused on three main strategies: depletion (e.g., anti-CD25, anti-CCR4, or anti-CCR8 antibodies), functional blockade (e.g., targeting CTLA-4 or TIGIT), and disruption of metabolic pathways (e.g., adenosine or PI3K signaling) that support Tregs' biological functions. Although preclinical studies have shown that targeting Tregs have antitumor effects, clinical trials have demonstrated variable efficacy and toxic effects, reflecting the fine balance between immune activation and tolerance. Newer approaches aim to selectively impair intratumoral Tregs while preserving peripheral immune control, guided by T-cell subsets such as FOXP3+Helios+CCR8+ cells, which may help predict therapeutic response. A deeper understanding of Treg regulation is needed to unlock their therapeutic potential without compromising immune equilibrium.
Radio-resistance hinders the effectiveness of radiotherapy for treating colorectal cancer (CRC) patients. Metadherin (MTDH) is proposed to exert a pivotal role in resistance to radiotherapy in various malignancies. This study aims to investigate the precise impact of MTDH on CRC radio-resistance. Through a fusion of 14 machine learning algorithms and SHapley Additive exPlanations (SHAP) interpretability analysis, we pinpointed MTDH as a pivotal gene implicated in radio-resistance mechanisms. Subsequently, we investigated MTDH expression in CRC tissues using single-cell RNA sequencing data (scRNA-seq) and bulk transcriptomic data. MTDH level was also examined in tissues from 82 rectal cancer patients who were responsive or non-responsive to radiotherapy. We established radioresistant variants of SW480 and HT29 cells (designated SW480-R and HT29-R), then evaluated their characteristics using cell viability assays, apoptosis measurements, and γ-H2AX foci immunofluorescence. Then, MTDH silencing in radioresistant cells was applied to further investigate the impact of MTDH on regulating radiosensitivity for CRC cells. Machine learning analysis revealed a significant association between MTDH and radio-resistance. Furthermore, multi-omics data confirmed that MTDH expression was significantly upregulated in CRC tissues and, more notably, within the more malignant diploid single-cell subpopulation. Genes associated with MTDH were predominantly enriched in pathways related to damage repair, DNA damage response, epithelial-mesenchymal transition (EMT), and stem cell differentiation, which were known to be critically involved in radio-resistance. Experimental validation confirmed significantly elevated MTDH expression in both radioresistant rectal cancer specimens and corresponding cellular models. High level of MTDH was positively related to several clinicopathological parameters, including tumor stage, differentiation, and lymph node status. Silencing of MTDH inhibited proliferative ability, increased apoptosis, and increased γ-H2AX foci numbers in CRC cells with radiation treatment. This study emphasizes the potential of MTDH as a promising prognostic and therapeutic target in response to radiotherapy for treating CRC patients.
Extrachromosomal DNA (ecDNA) constitutes a principal factor in the amplification of oncogenes and the progression of tumors in solid malignancies. This review synthesizes emerging mechanistic, genomic, and immunologic evidence across multiple tumor types, including glioblastoma, lung, breast, gastrointestinal, hepatobiliary, urothelial, prostate, gynecologic, pediatric, and head-and-neck cancers, with the goal of clarifying the role of ecDNA in immune escape and therapy resistance and outlining its translational implications for precision oncology. ecDNA comprises substantial acentromeric circular elements that serve as transcriptional hubs, modulate enhancer-promoter interactions, and undergo dynamic copy-number cycling, thereby fostering intratumoral heterogeneity and resistance to therapy. Recurrent oncogenic cargos, including epidermal growth factor receptor (EGFR), v-myc avian myelocytomatosis viral oncogene homolog (MYC), erb-b2 receptor tyrosine kinase 2, also known as human epidermal growth factor receptor 2 (ERBB2/HER2), and cyclin D1 (CCND1), are frequently located in ecDNA. They can interconvert with intrachromosomal homogeneously staining regions (HSRs) under treatment pressure. Emerging evidence links ecDNA to an immune-cold phenotype, characterized by downregulation of antigen presentation and decreased responsiveness to immune checkpoint inhibitors. We further emphasize diagnostic and translational methodologies that incorporate ecDNA detection through liquid biopsy and the spatial mapping of tumor topology. Finally, we propose a comprehensive clinical implementation framework that integrates ecDNA profiling, longitudinal monitoring, and immune microenvironment assessment to guide precision therapy. Gaining a deeper understanding of ecDNA biology has the potential to ultimately transform it from merely a prognostic biomarker into a targetable element within cancer therapy.
KRAS mutations are commonly found in 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making it one of the deadliest cancers. Key oncogenic signaling networks, such as KRAS, TP53-MDM2, EGFR, and PI3K/AKT/mTOR, are frequently altered in this invasive disease. These networks function within a dense desmoplastic tumor environment that inhibits drug delivery and fosters therapeutic resistance. Although KRAS mutations are a primary oncogenic driver and occur in approximately 90% of patients with PDAC, variant-specific biology (e.g., G12D, G12R, G12V, and G12C) affects downstream signaling dependency and treatment response. Although specific KRASG12C inhibitors have been developed, their use in PDAC remains limited because of compensatory pathway activation and mutation prevalence. Similarly, whereas EGFR amplification and adaptive signaling bypass pathways decrease the durability of EGFR-targeted therapies, TP53 inactivation and MDM2 axis dysregulation contribute to genomic instability and treatment resistance. Although resistance to chemotherapy and targeted therapies, survival signaling, and metabolic reprogramming are all significantly affected by the PI3K/AKT/mTOR system, the therapeutic results with pathway inhibitors have been mixed. Significantly, these signaling pathways function within a coordinated, interdependent network, wherein single-agent approaches are compromised by crosstalk and feedback activation. This review synthesizes these main signaling axes, emphasizing molecular pathology, including mutation-specific biology, diagnostic techniques such as liquid biopsy and NGS, the role of natural compounds, the tumor microenvironment (TME) in pancreatic cancer (PC), and the limitations noted in therapeutic trials. Novel therapeutic approaches include KRAS-directed degradation techniques, pathway co-inhibition, rational combination methods, and therapy paradigms driven by the TME. To discover new molecules with long-lasting therapeutic effects, a system-level understanding of pathway interactions within the PDAC microenvironment is necessary.
Cancer cells are more susceptible to oxidative damage due to their reliance on tightly regulated redox homeostasis. Sulfiredoxin (Srx) is an antioxidant enzyme that restores hyperoxidized peroxiredoxins and contributes to cellular redox regulation. Previously, we demonstrated that pharmacological inhibition of Srx induces preferential death of cancer cells and tumor regression by weakening antioxidant defenses. In this study, we investigated the anticancer efficacy of LMT328, a more potent Srx inhibitor developed through molecular modeling. LMT328 exhibited greater efficacy than the previously reported inhibitor J14 in inhibiting cellular Srx activity, elevating intracellular oxidative stress, inducing mitochondrial damage, and triggering apoptotic cell death in cancer cells. These effects were attenuated by ectopic Srx expression or antioxidant treatment, supporting that LMT328 exerts its cytotoxic effects through oxidative stress resulting from Srx inhibition. Notably, LMT328 induced greater oxidative stress, mitochondrial damage, and cytotoxicity in tumorigenic T80H cells compared with nontumorigenic T80 cells. In a xenograft model, LMT328 significantly suppressed tumor growth with minimal toxicity. Collectively, our findings demonstrate that LMT328 disrupts Srx-dependent redox homeostasis, leading to oxidative stress-associated mitochondrial damage and cancer cell death, and suggest that targeting Srx may represent a promising strategy for redox-based cancer therapy.
IntroductionLow- and middle-income countries (LMICs) like Nigeria face rising cancer incidence and mortality, with late-stage presentation and limited resources. Only eight government-funded radiotherapy centres serve a population of 223.8 million-far below the estimated 280 radiotherapy machines required. To increase patient throughput we evaluated integration of AI auto-contouring tools to expedite treatment planning, specifically target and organ-at-risk delineation.Materials and MethodsWe performed an observational, survey-based study of radiation oncology staff at our Cancer Centre. Participants were consultant and resident oncologists and medical physicists. The survey compared time spent using AI auto-contouring versus manual contouring and collected perceptions of impact, benefits, and limitations.ResultsThirty-one staff responded: 20 (64.5%) oncologists and 11 (35.5%) medical physicists. Experience with AI varied (33% ≤ 6 months; 13% ≈2 years). Respondents reported increased confidence in planning: 11 (35%) moderate, 12 (39%) moderate-high, and 8 (26%) high. Common limitations were licence availability (20, 64.5%) and technical expertise (19, 61.3%). Most respondents (20, 65%) would recommend the tool. The principal benefit was improved workflow efficiency (25, 81%). AI-assisted planning significantly reduced planning time for most tumour sites; sites with complex anatomy showed no time benefit, reflecting the need for intensive manual correction.ConclusionDeployment of AI auto-contouring at a Nigerian cancer centre reduced planning time for most sites and improved clinician confidence, but complex anatomical regions still require detailed manual oversight and additional AI training. AI tools can increase throughput in LMIC radiotherapy services, though licensing, infrastructure, and training barriers exist and must be addressed to ensure safe implementation. Future work should include multi-centre validation, formal inter-rater reliability assessment, and prospective patient-level outcome evaluation and cost-effectiveness analyses.
Antibody-drug conjugates (ADCs) combine the target specificity of monoclonal antibodies with the cytotoxic potency of small-molecule payloads. In recent years ADCs have emerged as a clinically validated component of modern precision oncology. To date, more than a dozen ADCs have received FDA approval for oncologic indications, with additional agents approved regionally and hundreds of ADC-based regimens in clinical development. Collectively, these therapies have demonstrated clinical benefit across hematologic malignancies and solid tumors, including significant overall survival improvements in advanced phase clinical trials. In this Trial Watch, we provide an overview on available ADCs from early preclinical development to current clinical applications. We also summarize design principles underpinning clinically successful ADCs, including epitope targeting, linker chemistry, payload toxicity and drug-to-antibody ratio, and discuss how these features can influence pharmacokinetics, intracellular trafficking, bystander effect and toxicity. Finally, we discuss results from advanced-stage clinical trials and approved agents to define future directions.
Urological cancers exhibit significant sex differences in incidence, treatment response, and prognosis, with males generally showing higher morbidity and mortality. This review systematically summarizes the underlying molecular and clinical mechanisms of these disparities, focusing on sex hormones, chromosome biology, tumor immune microenvironment, and microbiota. Sex hormones modulate key tumor processes including proliferation, apoptosis, non-apoptotic cell death, and DNA repair. Genetic factors such as X chromosome inactivation escape genes and Y chromosome loss also contribute to sex-biased cancer susceptibility. Furthermore, sex-specific differences in the urinary system and gut microbiota influence local immunity and inflammation, thereby affecting tumor progression and therapeutic response. Lifestyle and environmental factors, including smoking, alcohol consumption, and occupational exposures, further exacerbate these disparities. Clinically, sex differences impact the efficacy of immunotherapy and targeted therapies, underscoring the need for sex-informed treatment strategies. Integrating sex as a biological variable in research, clinical practice, and public health policies is essential for advancing precision oncology in urologic cancers.
Lack of response to neoadjuvant chemoradiotherapy (nCRT) has been described as a surrogate of aggressive tumor biology leading to poor oncologic outcomes in locally advanced rectal cancer (LARC). However, there is a paucity of data on this association for LARC patients undergoing pelvic exenteration (PE). The National Cancer Database was queried for adults with cT4 rectal adenocarcinoma between 2006-2021. Three groups were identified: upfront PE, nCRT with neoadjuvant rectal (NAR) score <8 followed by PE, and nCRT with NAR≥8 followed by PE. The NAR score is a validated endpoint that incorporates cT, pT, and pN to calculate treatment efficacy. Of 942 patients, 73% were <65 years old, 57% female, 84% white with a median follow-up of 40 (0-201) months; 5% underwent upfront PE, 82% nCRT with NAR≥8, and 13% nCRT with NAR<8. Overall, 15% had positive margins. On univariable analysis, compared to NAR<8, upfront PE and NAR≥8 were significantly associated with increased odds of a positive surgical margin. Five-year OS was 84% for NAR<8, 55% for NAR≥8, and 28% for upfront PE. After adjustment, upfront PE (HR 5.10, 95% CI 2.69-9.65) and NAR≥8 (HR 2.23, 95% CI 1.31-3.79) cohorts experienced worse overall survival (OS). In this US-based cohort of LARC undergoing PE, tumor regression after nCRT was strongly associated with lower rates of positive margins and better overall survival, confirming its significant relevance in the selection and management of these patients.
Brentuximab vedotin combined with doxorubicin, vinblastine, and dacarbazine (A-AVD) improves outcomes in advanced-stage classic Hodgkin lymphoma, but patients with a positive early interim PET have inferior prognosis. We evaluated whether very early [18F]fluorodeoxyglucose ([18F]FDG)-PET-guided treatment adaptation after one cycle of A-AVD improves activity while limiting exposure to intensive chemotherapy. This single-arm, multicentre, phase 2 trial was conducted at 16 centres in seven countries (the Netherlands, Spain, Denmark, Belgium, Portugal, Slovakia, and Poland). Adults aged 18-60 years with previously untreated advanced-stage classic Hodgkin lymphoma, WHO performance status 0-2, and adequate organ function received one cycle of A-AVD (brentuximab vedotin 1·2 mg/kg intravenously, doxorubicin 25 mg/m2 intravenously, vinblastine 6 mg/m2 intravenously, and dacarbazine 375 mg/m2 intravenously, all on days 1 and 15), followed by centrally reviewed [18F]FDG-PET-CT (PET1). PET1-negative (Deauville score 1-3) patients received five additional A-AVD cycles; PET1-positive (Deauville score 4-5) patients switched to six cycles of BrECADD (brentuximab vedotin 1·8 mg/kg intravenously on day 1; etoposide 150 mg/m2 intravenously on days 2-4; cyclophosphamide 1250 mg/m2 intravenously on day 2; doxorubicin 40 mg/m2 intravenously on day 2; dexamethasone 40 mg orally on days 2-5; dacarbazine 250 mg/m2 intravenously on days 3-4). The primary endpoint was 2-year modified progression-free survival (mPFS), defined as the proportion of patients alive and free of progression, relapse, or death from treatment start, with initiation of new systemic therapy for persistent disease counted as an event. Analyses were prespecified and conducted in the evaluable population (registered and eligible patients, who commenced the allocated treatment according to PET1 results after 1 cycle of A-AVD). The safety population consists of all patients who started A-AVD treatment (ie, received at least one dose of study therapy). This is the primary analysis of a completed trial. This trial is registered on ClinicalTrials.gov (NCT03517137) and EudraCT 2017-000498-35). From Aug 1, 2019, to Aug 31, 2021, we enrolled 150 patients (81 males [54%] and 69 females [46%]; median age 32 years [IQR 23-39]) who received one cycle of A-AVD, after which 90 (60%) of them had a negative PET1 and 60 (40%) a positive result. 145 were evaluable for efficacy; the median follow-up at the clinical cutoff (Sept 1, 2023; database lock Dec 11, 2023) was 30·1 months (IQR 24·6-36·4). 16 patients experienced an mPFS event. The estimated 2-year mPFS was 89·5% (80% CI 85·7-92·4). The most common grade 3-4 adverse event was neutropenia (53 [35%] of 150) followed by anaemia (18 [12%]) and peripheral sensory neuropathy (nine [6%]). Serious adverse events occurred in 45 (30%) of 150 patients. No deaths occurred. Very early PET-guided intensification with BrECADD yields high activity in advanced-stage classic Hodgkin lymphoma while sparing most patients intensive chemotherapy. Takeda Oncology.
Colorectal cancer (CRC) remains one of the leading causes of cancer mortality, with a poor survival rate of less than 15%. Imatinib (IM) and Zebularine (ZEB) alone have shown potential effects in CRC treatment, but their combination has not been thoroughly studied. This study investigates the potential effects of IM and ZEB in colon cancer cells to provide a novel therapeutic agent for managing CRC. Cell growth inhibition, oxidative stress markers, and cell cycle progression were assessed in HCT-116 cells treated with IM, ZEB, and their combinations. ZEB uptake levels were analyzed by LC-MS/MS, apoptosis was quantified by flow cytometry, and gene expression changes were analyzed by qPCR. The expression of metastatic markers, apoptotic regulators, and EGFR was assessed. Both IM and ZEB inhibited cell growth in a concentration-dependent manner, and their combination showed synergistic effects. The combination significantly enhanced oxidative stress. The combination therapy increased apoptosis and necrosis. Furthermore, the combination induced significant S-phase arrest in the cell cycle. The combination treatment reduced metastatic markers (MMP9, MMP2), and the apoptotic marker Caspase-9 was upregulated. Additionally, the Bcl-2 protein, a key regulator of apoptosis, was significantly downexpressed. Remarkably, the combination treatment showed significant inhibition in EGFR levels. Both IM and ZEB combination showed promise in the management of CRC by inducing oxidative stress, promoting apoptosis, and modulating critical genes involved in metastasis and apoptosis. Further investigation will be needed to verify their application in preclinical and clinical settings.