Oncology Research最新文献

Background: Glioblastoma (GBM) prognosis has seen little improvement over the past two decades. While immunotherapy has revolutionized cancer treatment, its impact on GBM remains limited. To characterize the evolving research landscape and identify future directions in GBM immunotherapy, we conducted a comprehensive bibliometric review.

Methods: All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection. CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.

Results: Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions, published in 945 journals. The United States produced the highest number of publications, while Switzerland achieved the highest average citation rate. Duke University led in institutional output and citations. John H Sampson was the most productive author, and Roger Stupp was the most cited. Frontiers in Immunology published the most papers, while Clinical Cancer Research was the most cited journal. Research focus centered on adoptive T cell therapy, particularly chimeric antigen receptor (CAR)-T cells with 572 dedicated publications. Within CAR-T research for GBM, the University of Pennsylvania was the leading institution, Frontiers in Immunology the predominant journal, and Christine E Brown (City of Hope National Medical Center) was the most prolific and cited author.

Conclusions: There has been a growing interest in GBM immunotherapy over past decades. The United States is the dominant contributor. CAR-T therapy represents the primary research focus. Emerging strategies like chimeric antigen receptor-modified natural killer (CAR-NK) cells, chimeric antigen receptor-engineered macrophages (CAR-M), and cytomegalovirus-specific T cell receptor (CMV-TCR) T cells are gaining prominence, aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have transformed the management of hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer, yet evidence for elderly or poor-performance patients remains limited. This study examined real-world outcomes of palbociclib plus endocrine therapy in Asian patients, with additional subgroup analyses by age and performance status.

Methods: We retrospectively analyzed 46 consecutive Asian patients with recurrent or de novo HR+/HER2- breast cancer treated with first-line palbociclib plus ET between April 2021 and March 2025. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), disease control rate (DCR), and safety. Subgroup analyses were performed by age (<70 vs. ≥70 years) and performance status (PS; 0-1 vs. 2-3).

Results: The median PFS was 26.6 months (range, 1.4-69.5). Stratified by age, median PFS was 26.9 months in patients <70 years and 26.2 months in those ≥70 years (p = 0.760). By PS, PFS was 26.9 months for PS 0-1 and 17.8 months for PS 2-3 (p = 0.099). ORR was 60.9% and DCR 93.5%; notably, all PS 2-3 patients achieved disease control. Hematologic toxicities were common, with neutropenia (80.4%) and leukopenia (86.7%) predominating, but grade ≥ 3 anemia was rare (2.2%). Elderly patients experienced anemia more frequently, while overall toxicity remained manageable. Dose reductions occurred in 47.8% without loss of efficacy.

Conclusions: In routine Japanese practice, palbociclib plus ET provided prolonged PFS and high disease control consistent with pivotal trials and international real-world evidence. Importantly, elderly patients tolerated treatment well, and selected PS 2-3 patients also derived clinical benefit. These findings indicate that neither age nor PS alone should preclude the use of palbociclib in carefully monitored real-world patients.

Background: Breakpoint Cluster Region-Abelson (BCR::ABL1) fusion protein is essential in the pathogenesis of chronic myeloid leukemia (CML); however, the chronic-to-blast phase transformation remains elusive. We identified novel kinesin light chain 2 (KLC2) mutations in CML-myeloid blast phase patients. We aimed to examine the functional role of KLC2 mutations in leukemogenesis.

Methods: To evaluate the biological role of KLC2 mutants (MT) in CML cells, we expressed KLC2-MT in different human CML cell lines harboring BCR::ABL1 and performed immunoblot, immunofluorescence, cell proliferation, differentiation, and apoptosis; Tyrosine kinase inhibitor (TKI)-drug activities; and clonogenic assays for in vitro functional analyses. We co-expressed KLC2-MT and BCR::ABL1 in mouse bone marrow cells (BMCs) to evaluate their clonogenic and self-renewal abilities ex vivo. Furthermore, we examined tumorigenic activity and drug efficacy in the K562 xenograft model.

Results: KLC2-MT overexpression in BCR::ABL1-positive K562 and KU812 CML cells promoted cell proliferation and clonogenic potential, decreased imatinib sensitivity, and reduced apoptosis. Serial colony replating assays revealed that KLC2-MT and BCR::ABL1 co-expression enhanced the self-renewal ability of mouse BMCs with immature morphology. In the K562 xenograft model, KLC2-MT enhanced tumorigenic potential and diminished imatinib efficacy. Further studies reported that KLC2-MT augmented signal transducer and activator of transcription 3 (STAT3) activation and nuclear accumulation in imatinib-treated CML cells. KLC2-WT and KLC2-MT interacted with mothers against decapentaplegic homolog 2 (SMAD2); however, the latter impaired transforming growth factor-beta (TGF-β)-mediated SMAD2/3 activation while enhancing STAT3 phosphorylation.

Conclusions: This study demonstrates the biological and functional importance of KLC2 mutation in CML cells, potentially enabling the development of better treatment strategies for CML patients carrying KLC2 mutations and providing enhanced understanding of the disease progression.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms, with a particular focus on mitochondrial function and apoptosis.

Methods: Differential expression analyses were performed across three datasets-The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (LIHC), GSE36076, and GSE95698-to identify overlapping differentially expressed genes (DEGs). A prognostic risk model was then constructed. Cysteine/serine-rich nuclear protein 1 (CSRNP1) expression levels in HCC cell lines were assessed via western blot (WB) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effects of CSRNP1 knockdown or overexpression on cell proliferation, migration, and apoptosis were evaluated using cell counting-8 (CCK-8) assays, Transwell assays, and flow cytometry. Mitochondrial ultrastructure was examined by transmission electron microscopy, and intracellular and mitochondrial reactive oxygen species (mROS) levels were measured using specific fluorescent probes. WB was used to assess activation of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) pathway, and pathway dependence was examined using the ROS scavenger N-Acetylcysteine (NAC) and the JNK inhibitor SP600125.

Results: A six-gene prognostic model was established, comprising downregulated genes (NR4A1 and CSRNP1) and upregulated genes (CENPQ, YAE1, FANCF, and POC5) in HCC. Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis. Conversely, CSRNP1 overexpression impaired mitochondrial integrity, increased both mitochondrial and cytoplasmic ROS levels, and activated the JNK/p38 MAPK pathway. Notably, treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.

Conclusion: CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC. It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner. These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.

Background: Therapeutic responses of breast cancer vary among patients and lead to drug resistance and recurrence due to the heterogeneity. Current preclinical models, however, are inadequate for predicting individual patient responses towards different drugs. This study aimed to investigate the patient-derived breast cancer culture models for drug sensitivity evaluations.

Methods: Tumor and adjacent tissues from female breast cancer patients were collected during surgery. Patient-derived breast cancer cells were cultured using the conditional reprogramming technique to establish 2D models. The obtained patient-derived conditional reprogramming breast cancer (CRBC) cells were subsequently embedded in alginate-gelatin methacryloyl hydrogel microspheres to form 3D culture models. Comparisons between 2D and 3D models were made using immunohistochemistry (tumor markers), MTS assays (cell viability), flow cytometry (apoptosis), transwell assays (migration), and Western blotting (protein expression). Drug sensitivity tests were conducted to evaluate patient-specific responses to anti-cancer agents.

Results: 2D and 3D culture models were successfully established using samples from eight patients. The 3D models retained histological and marker characteristics of the original tumors. Compared to 2D cultures, 3D models exhibited increased apoptosis, enhanced drug resistance, elevated stem cell marker expression, and greater migration ability-features more reflective of in vivo tumor behavior.

Conclusion: Patient-derived 3D CRBC models effectively mimic the in vivo tumor microenvironment and demonstrate stronger resistance to anti-cancer drugs than 2D models. These hydrogel-based models offer a cost-effective and clinically relevant platform for drug screening and personalized breast cancer treatment.

Objectives: B-cell maturation antigen (BCMA)-targeted antibody-drug conjugates (ADCs) have emerged as promising therapies for relapsed/refractory multiple myeloma (RRMM), but the overall efficacy and safety profile is unclear. This study aimed to synthesize the available evidence on the safety and efficacy of BCMA-ADCs in development for RRMM.

Methods: A systematic search was conducted using six bibliographic databases and ClinicalTrials.gov up to November 2024. Studies were eligible if they were human clinical trials or animal studies evaluating BCMA-ADCs and reported efficacy and safety outcomes. Data extraction and quality assessments were conducted using validated tools, including ROBINS-I and SYRCLE's risk of bias tool.

Results: A total of 21 studies were included: 16 clinical trials and five animal studies. Key findings included that belantamab mafodotin demonstrated variable but generally durable response rates (32%-85%) and a broad range of progression-free survival (PFS) (2.8-36.6 months), albeit with ocular toxicities in 51%-96%. Among newer candidates, MEDI2228 showed median PFS 5.1-6.6 months with 14% discontinuation for ocular symptoms, while AMG 224 had an overall response rate (ORR) of 23% (9/40) with anemia 21%, thrombocytopenia 24%, and ocular adverse events (AEs) 21%. Animal studies supported the tumor-eradicating potential of all BCMA-ADC candidates, although safety signals such as hepatic and renal toxicity were noted with HDP-101. The risk of bias assessment revealed generally moderate to serious concerns in human trials, while the overall quality of the animal studies was acceptable.

Conclusions: BCMA-targeted ADC candidates show encouraging efficacy in RRMM, particularly belantamab mafodotin. However, frequent AEs, especially ocular and hematologic toxicities, underscore the need for optimization in ADC design. Further research should prioritize enhancing safety while maintaining clinical benefit.

Background: While the treatment of metastatic renal cell carcinoma (mRCC) is evolving due to immune checkpoint inhibitors (ICIs), optimal strategies for later lines of therapy have yet to be defined. The combination of lenvatinib and everolimus represents a viable option, and the present review aimed to summarize its activity, effectiveness, and safety.

Methods: A systematic review of the literature was conducted using PubMed, targeting studies published between 2018 and 2025. Eligible studies included English-language prospective and retrospective trials reporting survival outcomes in mRCC patients treated with lenvatinib and everolimus after at least one ICI-containing regimen.

Results: Nine studies met the inclusion criteria, encompassing a total of 441 patients. The lenvatinib and everolimus combination was primarily used in the third and subsequent lines of therapy. Median overall survival ranged from 7.5 to 24.5 months, while median progression-free survival was more consistent, between 6.1 and 6.7 months, except for one study reporting 12.9 months. Objective response rates varied widely (14.0%-55.7%). Adverse events of grade ≥ 3 did not exceed the expected rate, with diarrhoea and proteinuria as the most reported events. Dose reductions and treatment discontinuations due to toxicity occurred but were generally lower than in prior pivotal trials.

Conclusions: Real-world evidence suggests that lenvatinib and everolimus represent an effective and safe option after ICI failure in mRCC patients. Nevertheless, the lack of randomized phase III trials and the heterogeneity of existing studies highlight the need for more robust prospective research to guide post-ICI therapeutic strategies.

Background: A significant proportion of patients still cannot benefit from existing targeted therapies and immunotherapies, making the search for new treatment strategies extremely urgent. In this study, we combined integrate public data analysis with experimental validation to identify novel prognostic biomarkers and therapeutic targets for lung adenocarcinoma (LUAD).

Methods: We analyzed RNA and protein databases to assess the expression levels of cytochrome C oxidase 5B (COX5B) in LUAD. Several computational algorithms were employed to investigate the relationship between COX5B and immune infiltration in LUAD. To further elucidate the role of COX5B in LUAD, we utilized multiple experimental approaches, including quantitative reverse transcription PCR assays, western blot, immunohistochemistry, electron microscopy, flow cytometry, and EdU proliferation assays.

Results: We revealed that COX5B was significantly elevated in LUAD and positively correlated with poor prognosis of LUAD patients. Analysis of co-expression network indicated that COX5B may take part in the intracellular adenosine triphosphate (ATP) synthesis through the oxidative phosphorylation pathway. There was a negative correlation between COX5B expression and immune infiltration in LUAD. Furthermore, we validated that COX5B levels were significantly elevated in both LUAD tissues and cell lines. Specifically, immunohistochemistry (IHC) assays revealed a 2.32-fold increase of COX5B in tumor tissues compared to that in adjacent normal tissues (p = 0.0044). Additionally, COX5B knockdown disrupted the redox homeostasis, ultimately suppressed the proliferation of LUAD cells. Subsequent investigations demonstrated that berberine effectively targeted COX5B, diminishing its protein expression and consequently inhibiting cell proliferation and tumor growth in LUAD.

Conclusions: This study established that upregulated COX5B was positive associated with poor patient prognosis in LUAD, elucidating the mechanisms by which berberine targets COX5B to inhibit tumor growth, thereby providing a novel therapeutic target and strategy for the clinical management of LUAD.

[This retracts the article DOI: 10.3727/096504016X14765492198706.].

Objectives: Ribosomal protein S6 kinase A2 (RPS6KA2) has been identified as a potential prognostic biomarker in several cancers, including breast cancer, glioblastoma, and prostate cancer. However, its functional significance in ovarian cancer is not well characterized. This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer, particularly in relation to cisplatin resistance.

Methods: The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR, immunofluorescence staining, immunohistochemistry, and western blotting. Prognostic associations were conducted using the Kaplan-Meier Plotter database. Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity. Ferroptosis-related parameters, including intracellular iron content, glutathione (GSH) levels, reactive oxygen species (ROS) generation, and mitochondrial membrane potential, were measured to determine ferroptotic changes. In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents.

Results: Using ovarian cancer cell lines and clinical tissue samples, we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts. Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance. Mechanistically, RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) signaling pathway, which in turn increased sensitivity to cisplatin. Additionally, RPS6KA2 facilitated ferroptosis, contributing to its tumor-suppressive function. miR-512-3p was identified as a negative regulator of RPS6KA2, driving cisplatin resistance through suppression of RPS6KA2 expression. In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models.

Conclusion: These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.