Cancer Science最新文献

The global Phase 3 IMpower010 study (NCT02486718) evaluated atezolizumab versus best supportive care (BSC) after complete resection and adjuvant platinum-based chemotherapy in patients with stage IB-IIIA non-small cell lung cancer (NSCLC). We report updated efficacy and safety results from the disease-free survival (DFS) final and overall survival (OS) second interim analyses, with ≥ 5 years of follow-up in Japanese patients. Patients who received 1-4 21-day chemotherapy cycles after surgery were randomized 1:1 to receive atezolizumab 1200 mg every 3 weeks (≤ 16 cycles) or BSC. Of 149 patients enrolled, 117 were randomized to the intention-to-treat (ITT) population (atezolizumab n = 59; BSC n = 58). At data cutoff (January 26, 2024), unstratified hazard ratios (HRs) (95% confidence interval [CI]) for DFS in the atezolizumab versus BSC arms were 0.54 (0.28-1.07) in the stage II-IIIA programmed death-ligand 1 (PD-L1) tumor cell (TC) ≥ 1% (n = 74), 0.64 (0.27-1.52) in the stage II-IIIA PD-L1 TC 1%-49% (n = 34), 0.52 (0.17-1.54) in the stage II-IIIA PD-L1 TC ≥ 50% (n = 40), 0.58 (0.34-1.00) in the stage II-IIIA all-randomized (n = 113), and 0.57 (0.34-0.98) in the ITT populations. OS remained immature; median OS was not reached in both treatment arms for all subgroups. Grade 3/4 adverse events occurred in 15 (26.8%) and 7 patients (12.1%) in the atezolizumab and BSC arms, respectively; no deaths were reported. In this exploratory subgroup analysis, adjuvant atezolizumab demonstrated numerically improved DFS and OS versus BSC in Japanese patients and was well tolerated, similar to the global IMpower010 population. Trial Registration: ClinicalTrials.gov identifier: NCT02486718.

The impact of achieving progression-free survival at 24 months (PFS24) on subsequent survival in patients with diffuse large B-cell lymphoma (DLBCL) relative to the general population remains debatable. We assessed the impact of achieving PFS24 in newly diagnosed DLBCL patients using data from JCOG0601, a prospective study of DLBCL patients treated with R-CHOP. Among 409 eligible patients (median follow-up: 5.3 years), 334 (82%) achieved PFS24, whereas 66 (16%) did not. Patients who achieved PFS24 had significantly better overall survival (OS) than those who did not (median OS, not reached vs. 1.3 years; p < 0.001). Similar results were observed for PFS12 and PFS60. The OS for patients after achieving PFS24 or PFS60 was not markedly different from that of the age-, sex-, and calendar period-matched Japanese general population (PFS24: standardized mortality ratio [SMR] 1.29, 95% confidence interval [CI] 0.72-2.12, p = 0.39; PFS60: SMR 1.43, 95% CI 0.47-3.33, p = 0.55). Conversely, the OS for patients after achieving PFS12 was significantly worse than that of the general population (SMR 2.30, 95% CI 1.59-3.22, p < 0.001). The primary cause of death among patients who achieved PFS12 was DLBCL, whereas the mortality rate from DLBCL among those who achieved PFS24 or PFS60 was less than 5%. Multivariable analysis showed that having two or more extranodal involvements (OR 2.76 [95% CI 1.39-5.46], p = 0.004) was the only significant risk factor for failing to achieve PFS24. Our findings suggest that PFS24 can serve as an early endpoint of OS in patients with DLBCL.

The bispecific antibody EMB-01 (bafisontamab), constructed using EpimAb's proprietary FIT-Ig platform, is designed to simultaneously target epidermal growth factor receptor (EGFR) and receptor tyrosine kinase Met (c-Met). Here, we characterize EMB-01's binding properties, mechanisms of action, and anti-tumor efficacy using in vitro cell line models and in vivo models (patient-derived xenografts, PDXs). EMB-01 exhibits high-affinity binding to EGFR and c-Met, induces co-degradation of both receptors, enhances endocytosis, and elicits strong antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effects. Mechanistically, EMB-01 effectively inhibits ligand-induced receptor phosphorylation, downstream AKT activation, and IL-8 secretion. Furthermore, EMB-01 demonstrates potent anti-tumor activity across multiple tumor models, outperforming existing EGFR-targeted therapies and other bispecific antibodies, while maintaining favorable pharmacokinetics with good tolerability in cynomolgus monkeys. These findings support the clinical development of EMB-01 as a promising therapeutic for EGFR/c-Met-driven cancers.

Nasopharyngeal carcinoma (NPC) is a malignant tumor characterized by significant radioresistance and poor clinical outcomes. EphA2, a protein frequently overexpressed in various malignancies, has been implicated in promoting tumor growth and metastasis. This study explored the role and mechanism of EphA2 in driving radioresistance in NPC and evaluated the therapeutic potential of the A11 peptide in overcoming this resistance. Clinical analysis of 104 NPC tissues (26 radioresistant and 78 radiosensitive) revealed that high EphA2 expression was significantly associated with radioresistance and independently predicted reduced overall survival. Functional studies using EphA2-knockdown NPC cell lines (5-8F and CNE2) demonstrated that silencing EphA2 enhanced radiosensitivity, as evidenced by in vitro assays including clonogenic formation, apoptosis analysis, and γ-H2AX detection, as well as in vivo xenograft experiments. Mechanistically, EphA2 drives radioresistance through a radiation-induced RSK-EphA2-AKT signaling cascade. Specifically, radiation triggered RSK-mediated phosphorylation of EphA2 at Ser897, which subsequently facilitated AKT phosphorylation at Ser473. The A11 peptide broke this signaling cascade by degrading EphA2 and blocking its S897 phosphorylation, thereby markedly enhancing radiosensitivity. These findings indicate that EphA2 overexpression and its S897 phosphorylation play a critical role in NPC radioresistance. The A11 peptide emerges as a promising therapeutic agent by degrading EphA2 and blocking its phosphorylation, offering a potential strategy to enhance radiotherapy efficacy and improve outcomes in NPC patients.

Cervical cancer is a prevalent malignancy among women, yet the involvement of neutrophils in its tumor microenvironment remains insufficiently explored. This study utilized single-cell RNA sequencing (scRNA-seq) to delineate neutrophil subsets and elucidate their roles in disease progression and prognosis. Analysis of 20 cervical biopsy samples across different disease stages identified five neutrophil subsets (N0-N4), among which the N4 subset exhibited a marked increase during disease advancement. Spatial transcriptomics and tissue microarray analyses revealed that N4 neutrophils are enriched in tumor regions and are associated with genes implicated in proliferation, metastasis, and immune evasion. Functional characterization demonstrated that N4 promotes tumor progression via activation of the Wnt signaling pathway and extracellular matrix remodeling. A neutrophil infiltration-based risk model was established and validated through multi-omics approaches, highlighting its potential in prognostic prediction. These findings underscore the pivotal role of N4 neutrophils in cervical cancer and provide valuable insights for the development of targeted immunotherapies and personalized treatment strategies.

Cancer-stromal interactions play important roles in the biology of various cancers, including lung adenocarcinoma. We aimed to comprehensively analyze the lung cancer interactome and identify the key ligand-receptor pairs involved in the aggressiveness of lung adenocarcinoma. Transcriptome data were obtained from xenografts of 11 lung cancer cell lines that represented the major driver mutations in lung adenocarcinomas. A quantitative dataset was constructed in both stroma-to-cancer and cancer-to-stroma directions using the cancer-stromal interactome analysis method. The prognostic value of each factor was evaluated using multiple datasets. Analysis of 24,250 stroma-derived mouse transcripts and 26,289 human cancer-derived transcripts identified 1150 cancer-stromal interactions, from which we selected 117 interactions based on the intensity score of ligand-stromal transcript levels. Further prognostic analysis using public databases led us to identify 21 ligand-receptor pairs, including well-known as well as less well-characterized ligand-receptor pairs. Therefore, we selected tumor necrosis factor superfamily member 12/tumor necrosis factor receptor superfamily member 12A as possible factors contributing to the aggressiveness of lung adenocarcinoma via cancer-stromal interactions; immunohistochemical analysis confirmed that these factors were expressed mainly in the stroma and cancer cells, respectively, in both xenografts and primary lung adenocarcinoma. In human clinical specimens, high tumor necrosis factor receptor superfamily member 12A expression significantly correlated with tumor size, invasive diameter, and stage. Thus, tumor necrosis factor superfamily member 12 and its receptor tumor necrosis factor receptor superfamily member 12A signaling axis may be potential candidates for therapeutic intervention for lung adenocarcinoma.

First-line atezolizumab combination therapies were approved for the treatment of metastatic non-small cell lung cancer (NSCLC) based on results from the global phase 3 trials IMpower130, IMpower132, and IMpower150. These trials reported 12-month overall survival (OS) rates of 60%-67% with atezolizumab combination therapy. J-TAIL-2 (NCT04501497), a prospective, multicenter, observational study, evaluated atezolizumab combination therapy in routine clinical practice in Japan. Patients ≥ 20 years old with NSCLC received atezolizumab plus carboplatin and nab-paclitaxel (atezo + CnP), atezolizumab plus carboplatin or cisplatin plus pemetrexed (atezo + PP), or atezolizumab plus bevacizumab plus carboplatin and paclitaxel (atezo + bev + CP) in clinical practice. The primary endpoint was the 12-month OS rate. Secondary endpoints included OS, progression-free survival, and subgroup analyses, including IMpower-unlike (did not meet the main eligibility criteria of each IMpower trial) and IMpower-like patients. In total, 814 patients were enrolled (atezo + CnP, n = 217; atezo + PP, n = 211; atezo + bev + CP, n = 386). The IMpower-unlike group included patients with Eastern Cooperative Oncology Group performance status ≥ 2, autoimmune disease, or interstitial lung disease. Twelve-month OS rates (95% confidence interval [CI]) were 62.9% (55.8-69.2), 72.1% (65.2-77.9), and 68.3% (63.2-72.9) with atezo + CnP, atezo + PP, and atezo + bev + CP, respectively. OS hazard ratios (95% CI) in the IMpower-unlike vs. -like subgroups were 1.36 (0.91-2.05), 1.08 (0.70-1.68), and 1.49 (1.09-2.06), respectively. No new safety signals were observed. Real-world efficacy and safety for each atezolizumab combination were comparable to those in the relevant IMpower trials.

Conventional cancer therapies, including radiation therapy and chemotherapy, rely on inflicting DNA damage, yet they inevitably affect normal cells, leading to severe adverse effects. The advent of precision chemotherapy exploiting tumor-specific DNA repair defects has validated the effectiveness of this approach. The first successful example is PARP inhibitors, which selectively kill homologous recombination (HR) defective cancers, such as familial breast cancer possessing HR deficiency due to BRCA gene mutations. However, the broader landscape of DNA maintenance-including DNA replication, repair, and checkpoint pathways-harbors numerous mutations in tumors that remain untargeted. Here, we propose repurposing chain-terminating nucleoside analogs (CTNAs) to target such cancers' vulnerabilities. CTNAs, long utilized as anti-cancers and anti-viral drugs, inhibit replication and thereby suppress growth, but their activity has never been systematically aligned with specific cancer mutations associated with DNA maintenance defects. Based on our recent studies, we demonstrate that CTNAs elicit synthetic lethality in cells deficient for distinct DNA maintenance systems, amplifying replication stress, leading to cell death. We highlight the spectrum of CTNA-induced lesions and repair pathways required for cellular tolerance. This framework presents a versatile "repair-defect-guided" chemotherapy that expands the clinical utility of CTNAs and improves therapeutic effect by reducing side effects.

Succinylation has been shown to promote lung cancer development, but its mechanism remains incompletely understood. KAT2A, a succinyltransferase, acts as an oncogene in multiple cancers, but its role in mediating lung cancer progression is unclear. This study aimed to investigate the mechanism by which KAT2A regulates lung cancer progression via succinylation. KAT2A expression was analyzed using UALCAN, GEPIA, and Kaplan-Meier Plotter databases, and validated in lung cancer cell lines and patient-derived tissues. Quantitative real-time PCR, Cell Counting Kit-8 (CCK-8), EdU staining, and flow cytometry were performed to assess KAT2A's role in lung cancer cell proliferation and apoptosis. KAT2A's target proteins were predicted using LinkedOmics and STRING databases. Additionally, in vivo xenograft models were established to evaluate the effect of KAT2A knockdown on tumor growth. Results indicated that KAT2A expression was significantly elevated in lung cancer cells and tissues and was associated with poor prognosis. KAT2A knockdown inhibited proliferation and promoted apoptosis in lung cancer cells, whereas MYC overexpression reversed these effects. Mechanistically, KAT2A knockdown downregulated MYC by reducing succinylation at K370 and K386 residues. Mutation of these sites abrogated the proliferative effect of MYC overexpression and restored apoptotic activity. Furthermore, in vivo experiments demonstrated that KAT2A knockdown inhibited tumor growth and reduced MYC succinylation. Our findings demonstrate that KAT2A functions as an oncogene in lung cancer by enhancing MYC succinylation. This study identifies KAT2A as a promising therapeutic target for lung cancer.