Cancer Science最新文献

Accumulating data demonstrate the robust overall and intracranial activity of trastuzumab deruxtecan (T-DXd) in HER2-positive breast cancer brain metastasis (BCBM). Limited data are available on HER2-low/zero BCBM, as well as patients with symptomatic active BM, leptomeningeal disease (LMD), and poor performance status. This multicenter, retrospective, real-world study enrolled patients diagnosed with HER2-positive or low/zero BCBM receiving T-DXd. Progression-free survival (PFS), intracranial progression-free survival (IC-PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), IC-ORR, IC-DCR, and adverse events (AEs) were evaluated. From January 2020 to July 2024, 58 HER2-positive and 30 HER2-low/zero patients were enrolled. In the HER2-positive cohort, the median PFS, IC-PFS, and OS were 11, 13, and 46 months, respectively. ORR and DCR were 65.2% and 91.3% systemically, with IC-ORR and IC-DCR of 61.0%/90.2% (RECIST 1.1) and 59.5%/88.1% (RANO-BM). In the HER2-low/zero cohort, median PFS, IC-PFS, and OS were 4, 5, and 26 months. ORR and DCR were 33.3% and 66.7%. IC-ORR and IC-DCR were 44.4% and 88.9% by RECIST 1.1 and RANO-BM. HR+/HER2-low patients had significantly longer PFS than HR-/HER2-low (10 vs. 3 months, p < 0.001). In the LMD cohort, the 12-month IC-PFS rates were 67.7% and 60.0% in HER2-positive and low/zero cohorts. The most common AEs included fatigue (45.9%) and appetite loss (25.2%). Seven (8.0%) patients suffered interstitial lung disease (ILD), including 2 (2.3%) grade 3. T-DXd showed substantial and durable overall and intracranial efficacy in HER2-positive and low/zero BCBM, including challenging subgroups with active BM or LMD.

Low-density lipoprotein receptor-related protein 11 (LRP11) is reported to be overexpressed in various cancers; however, its functional role in lung adenocarcinoma remains poorly understood. This study aimed to elucidate the tumor-promoting function of LRP11 in lung adenocarcinoma. We assessed the expression and function of LRP11 in lung adenocarcinoma cell lines through both silencing and overexpression experiments. RNA sequencing was performed to identify genes associated with LRP11 expression. The clinical relevance was evaluated using public datasets (The Cancer Genome Atlas and the Singapore Oncology Data Portal). LRP11 was overexpressed in lung adenocarcinoma cells and promoted their proliferation in vitro. RNA sequencing identified multiple genes negatively correlated with LRP11, all of which contained predicted C/EBPβ binding motifs in their promoter regions. Clinically, high LRP11 expression was associated with poor prognosis in patients with lung adenocarcinoma. In conclusion, LRP11 promotes lung adenocarcinoma progression by enhancing cell proliferation and modulating transcriptional activity. These findings suggest that LRP11 may serve as a potential therapeutic target and prognostic biomarker in lung adenocarcinoma.

Despite recent advances in neoadjuvant strategies for locally advanced rectal cancer (LARC), optimal chemotherapy regimens and the role of genetic biomarkers in guiding treatment remain unclear. Moreover, predictive markers are urgently needed for radiation-sparing strategies. Therefore, we aimed to assess the predictive and prognostic value of TP53, KRAS, and APC mutations in patients with LARC undergoing neoadjuvant chemotherapy (NACT) by retrospectively analyzing 43 patients with LARC who underwent NACT without radiation. Treatment response was assessed using RECIST criteria, revealing that 55.8% of patients exhibited a complete or partial response, which was significantly correlated with improved recurrence-free survival (p = 0.015). Conversely, tumor regression grade (TRG) did not predict survival outcomes. Targeted amplicon sequencing of pre-treatment biopsy and surgical specimens revealed high mutation frequencies in TP53 (74.4%), KRAS (44.1%), and APC (32.5%). TP53 mutations included diverse alterations, particularly gain-of-function missense variants, reflected in distinct immunohistochemical patterns. KRAS mutations mainly affected codon 12, and APC mutations were predominantly truncating. Notably, KRAS + APC co-mutations, observed in 11.6% of patients, were significantly associated with poor overall survival (p = 0.046), suggesting a synergistic role in poor prognosis. Conversely, patients with TP53 mutations exhibited improved survival (p = 0.007), underscoring their potential as favorable prognostic markers. Therefore, specific genetic alterations influence both prognosis and response to chemotherapy, offering critical insights into personalized treatment planning. Incorporating comprehensive molecular profiling—particularly TP53, KRAS, and APC mutation status—for preoperative evaluation may refine risk stratification, inform surgical decision-making, and support tailored therapeutic approaches in LARC.

Polyploid giant cancer cells (PGCCs) represent a unique and distinct subset of cancer cells, characterized by either an abnormally large nucleus or the presence of multiple nuclei within a single cell. An increasing body of evidence indicates that PGCCs are closely linked to cancer progression, therapeutic resistance, and poor clinical prognosis. However, despite their distinctive morphology, no universal marker has been identified to reliably distinguish PGCCs from other cancer cell populations. This is at least partly because PGCCs arise across various cancer types in diverse contexts, displaying considerable variability in their gene expression profiles. Nevertheless, they share key features, most notably polyploidy and remarkable stress resilience. The exceptional stress resilience of PGCCs arises from various mechanisms, including genome redundancy buffering against genetic damage, dormancy induction for survival in harsh conditions, gene expression changes enhancing hypoxia resistance, and metabolic adaptations supporting growth in resource-limited environments. Collectively, these properties make PGCCs highly resilient to stress, facilitating their persistence and contributing to the progression and aggressiveness of cancer. In this review, we provide a comprehensive discussion of the mechanisms underlying PGCC stress resilience and explore its broader implications for cancer pathogenesis. Understanding these adaptive strategies may offer new insights into cancer biology and reveal potential therapeutic targets to mitigate PGCC-driven malignancy.

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (EGFR Exon 20ins) are the third most common mutations in non-small cell lung cancer (NSCLC) and are associated with a poorer prognosis and resistance to conventional EGFR-tyrosine kinase inhibitors. This subpopulation analysis of the open-label phase 3 trial (PAPILLION) evaluates the efficacy and safety of amivantamab–chemotherapy versus chemotherapy among Japanese patients with locally advanced or metastatic NSCLC with EGFR Exon 20ins mutation (ClinicalTrials.gov, NCT04538664). Patients were randomized 1:1 to either intravenous amivantamab plus carboplatin/pemetrexed chemotherapy or chemotherapy alone. The primary endpoint was progression-free survival (PFS) by blinded independent central review; the secondary endpoints included objective response rate, duration of response, PFS after first subsequent therapy, overall survival, and safety. The overall population (n = 308) included 34 Japanese patients (amivantamab–chemotherapy, n = 19; chemotherapy, n = 15). Median PFS was 15.5 (95% CI 8.0, NE) months with amivantamab–chemotherapy compared with 5.6 (95% CI 3.0, 7.0) months (HR = 0.22 [0.09, 0.53]) for chemotherapy alone. Improvements in secondary endpoints were also greater in the amivantamab–chemotherapy arm than the chemotherapy arm. The predominant adverse events associated with amivantamab–chemotherapy were reversible hematologic and EGFR-related toxic effects; 2 of 19 patients discontinued all study agents due to treatment-emergent adverse events. Efficacy and safety results in this Japanese subpopulation were consistent with those in the overall population and support the first-line use of amivantamab–chemotherapy in this setting. Early identification of patients with EGFR Exon 20ins mutations, preferably with more sensitive next-generation sequencing-based methods, is important to ensure appropriate patient access to amivantamab–chemotherapy.

Trial Registration: ClinicalTrials.gov, NCT04538664.

Histone H3K4 modifications are altered in the regulation of gene expression and in multiple cellular processes during cancer development and progression. Understanding the roles of H3K4-modifying enzymes will provide novel insights into therapeutic tools for cancer treatment. H3K4-modifying enzymes catalyze the addition or removal of covalent modifications with specific substrate preferences. Although these proteins are evolutionarily conserved between yeast and mammals, their protein domains and functions are not identical, and they exhibit signs of evolutionary divergence. Recent studies have indicated that H3K4-modifying enzymes play non-canonical roles via non-histone substrates or non-catalytic functions. Here, we discuss both canonical and non-canonical functions of H3K4-modifying enzymes and their potential benefits for therapeutic applications in cancer therapy.

Cancer risk increases with age, and cellular senescence may be a major contributor to cellular carcinogenesis. Enormous efforts have been made to investigate the interrelation between aging and tumors, but little is known about the comparative features of normal aging, cellular senescence, and cancer at single-cell resolution. By integrating analyses of genomics, epigenomics, and bulk and single-cell transcriptomics, we revealed a directionally opposite transcriptional profile between cellular senescence and tumorigenesis at the single-cell level, which may be affected by epigenomic regulations. A total of 648 aging-dependent senescence-associated coregulated modules (SACMs), disproportionately affecting the reproductive systems of both females and males, were initially defined across 17 tissues. Single-cell analysis revealed that aging primarily affects endothelial cells, followed by T cells, epithelial cells, macrophages, and fibroblasts. Opposite directions of change in gene expression between aging and cancer can commonly be observed in endothelial, fibroblast, and epithelial cells, which may prompt the opposing patterns of gene expression between tissue aging and epithelial carcinoma at the bulk level. A similar pattern of expression can be observed in immune cells, which are characterized by decreased self-renewal with aging, but this pattern is reversed in epithelial carcinoma. Our study highlighted the role of senescence as a natural barrier against tumor formation and supported the idea that aging-related systemic environment changes create a protumorigenic milieu.

Primary cutaneous T-cell lymphoma (CTCL) manifests as a distinct variant of T-cell non-Hodgkin's lymphoma, predominantly impacting skin tissues and constituting approximately 75%–80% of cutaneous lymphoma cases, exhibiting diverse clinical presentations. Sezary syndrome (SS) is a rare subtype of CTCL. The therapeutic approach of SS frequently incorporates multiple chemotherapeutic compounds, encompassing specific histone deacetylase inhibitor agents. Nevertheless, similar to numerous chemotherapeutic protocols, existing monotherapy approaches for SS encounter limitations regarding sustained therapeutic outcomes and optimal effectiveness. This investigation seeks to examine the therapeutic impact and molecular pathways of combining Chidamide with LB100 in the treatment of SS. The synergistic effects of Chidamide and LB100 were evaluated in SS cell lines (Hut78 and H9) using the Cell Counting Kit-8, Chou-Talalay combination index, colony formation assays, and mouse xenograft models. Apoptosis was examined by Annexin V-APC/PI staining. The molecular mechanisms were explored through transcriptome sequencing, Western blotting, immunohistochemistry, and Lentivirus transfection. Chidamide and LB100 demonstrated synergistic antitumor activity in SS cell lines (Hut78 and H9) in vitro, with a combination index (CI) < 1. This synergy was also confirmed in Hut78 xenograft mice. Mechanistically, the two agents downregulated Tenascin C (TNC) and caused dephosphorylation of the PI3K/AKT/mTOR signaling cascade. This study also preliminarily validated the effect of the combination of the two drugs on other subtypes of CTCL. Overall, these findings provide potential new therapeutic strategies for CTCL (especially SS), although further clinical evaluation is required to validate these results.

Pancreatic cancer (PC) is associated with dismal clinical outcomes, largely due to the high prevalence of liver metastasis (LM) at diagnosis or post-resection. Despite its clinical significance, the molecular drivers of LM in PC remain poorly characterized, and few validated biomarkers or therapeutic targets are currently available. Our study identifies 7-dehydrocholesterol reductase (DHCR7), a terminal enzyme in cholesterol biosynthesis, as significantly upregulated in PC tissues and closely correlated with LM progression. In vitro experiments demonstrated that DHCR7 enhances the proliferation, invasion, and migration ability in PC cells, and in vivo experiments demonstrated that DHCR7 promotes LM of PC. The mechanism of DHCR7 promoting LM may be mediated by elevating cholesterol synthesis of PC cells and then activating the PI3K-Akt signaling pathway. Taken together, our findings uncover a novel molecular mechanism underlying LM in PC and highlight DHCR7 as a possible predictive biomarker or interventional target.

Ectopic germinal centers (GCs) are often formed in the thymus of patients with anti-acetylcholine receptor antibody (anti-AChR Ab)-positive thymic epithelial tumors (TETs) and are considered sites where B cells undergo affinity maturation to produce high-affinity anti-AChR Abs, contributing to the development of myasthenia gravis. To evaluate the clinical relevance of these ectopic GCs, we analyzed their distribution and associations with thymic involution and anti-AChR Ab titers using paraffin-embedded surgical specimens from 79 TET patients. Thymic involution was scored, and immunohistochemistry was performed to identify cells involved in GC formation. GCs were identified in 32 of the 79 cases. The anti-AChR Ab+ group had significantly higher frequencies of GCs in the residual thymus compared to the Ab− group. In all cases with GCs in the residual thymus, GCs were found both near the tumor and at distances greater than 1 cm from the tumor. Within the anti-AChR Ab+ group, GC+ patients were significantly younger and showed milder thymic involution than GC− patients. The number of GCs per unit area positively correlated with serum antibody titer. In Ab+ cases, AChR-α1 antigens were significantly more frequent in GC+ cases. In mildly involuted thymus, AChR antigens, antigen-presenting cells, and B cells were detected in the medulla, whereas these were rarely observed in severely involuted thymus. These findings suggest that GC formation occurs preferentially in a less involuted thymus and that surgical resection of at least the extent of a total thymectomy may be indicated in younger patients with anti-AChR Ab+ TETs.