Cancer research communications最新文献

Some anaplastic lymphoma kinase (ALK) gene rearrangement-positive lung cancers show early resistance, within 3 months, to alectinib. This study investigated the clinical and molecular characteristics of these patients. We analyzed patients with unresectable stage III/IV disease without indications for radical radiotherapy and recurrent ALK-positive lung cancer who received alectinib as the primary ALK tyrosine kinase inhibitor between 2013 and 2021 at nine hospitals. In total, 103 patients were included. The median age was 65 years; 44 were male and 22 had brain metastases. The median progression-free survival and overall survival (OS) were 28.7 and 80.6 months. Nineteen patients treated for ≤3 months and 84 treated for >3 months were categorized into the early resistance and responder groups, respectively. The early resistance group had significantly shorter OS (8.4 months vs. not estimable, P < 0.001) and was significantly more likely to have brain metastases (42% vs. 17%, P = 0.027). They also showed elevated inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR). Univariate analysis identified brain metastases and high NLR as significant predictors of early resistance. Spatial transcriptome analysis and immunohistochemical staining revealed upregulation of annexin A1 (ANXA1), a calcium-dependent phospholipid-binding protein involved in inflammation and cancer progression, in the early resistance group. Interleukin 6 stimulation, prompted by elevated inflammatory markers, increased ANXA1 expression and reduced alectinib sensitivity. Knockdown of ANXA1 improved alectinib sensitivity in alectinib-resistant cells. In conclusion, brain metastases and high NLR are associated with early resistance. ANXA1 may play an important role in mediating early resistance. New treatment options for the early resistance group are required.

Significance: Some ALK-positive lung cancers show early resistance to alectinib. This study found brain metastases and elevated NLR associated with early resistance. Spatial transcriptomics and functional analysis suggested involvement of ANXA1. These results reveal clinical and molecular biomarkers that may guide treatment strategies for early resistance to alectinib.

Epithelial ovarian cancer (EOC) represents the most lethal gynecologic malignancy, characterized by extensive tumor heterogeneity that contributes to treatment resistance and high recurrence rates. Recently, we developed SAIL66, a CLDN6-targeting T-cell engager currently in clinical evaluation for CLDN6-positive solid cancers, including EOC. Whereas CLDN6 is considered an attractive target for cancer therapy due to its cancer specificity, its biology remains poorly understood. In this study, we investigated the biological characteristics of CLDN6-positive EOC to identify its significance as a therapeutic target for ovarian cancer treatment. We demonstrated heterogeneous CLDN6 expression in xenograft and clinical tumors. In vitro-cultured ovarian cancer cell lines showed reversible changes in CLDN6 expression depending on cell density, accompanied by alterations in epithelial-mesenchymal transition (EMT)-related and stemness-related genes. Spatial transcriptomic analysis of clinical specimens revealed that CLDN6-positive areas formed both solid regions and dispersed small clusters within the same tumors, with differential expression of EMT-related and cell matrix remodeling genes between these areas, consistent with our in vitro observations at varying cell densities. Furthermore, carboplatin treatment increased CLDN6 expression, accompanied by changes in EMT-related genes. Leveraging these biological characteristics of CLDN6, we discovered that significant tumor regression was observed in mice treated with SAIL66 following carboplatin pretreatment. Post-carboplatin analysis revealed increased CLDN6 expression, EMT-related gene changes, and enhanced T-cell infiltration, which were associated with the synergistic effect of SAIL66. Our study provides insights into the biology and plasticity of CLDN6-positive cells in EOC heterogeneity and highlights the clinical significance of CLDN6-targeting therapies for ovarian cancer treatment.

Significance: CLDN6-positive ovarian cancer cells exhibit remarkable plasticity influenced by microenvironmental factors and chemotherapy, providing critical insights for understanding the biology of ovarian cancer progression and optimizing CLDN6-targeting therapy.

The miRNA microRNA-146a (miR-146a) regulates several aspects of chronic inflammation, including the hepatocellular carcinoma (HCC) risk factor, steatohepatitis. In this study, we find that the loss of miR-146a leads to a significantly increased tumor burden over a 9-month time frame in a mouse model of HCC. Notably, this miR-146a-/- phenotype is most pronounced in females, who are typically not sensitive to this model. Mechanistically, we identified increases in dysfunctional CD8+ T cells that express high levels of CCL5 and resemble age-associated T (Taa) cells, as well as elevated levels of myeloid cells with a myeloid-derived suppressor cell (MDSC) phenotype, a class of myeloid cells that suppresses tumor immunity. Deletion of Ccl5 from miR-146a-deficient mice returned tumor growth and the aberrant myeloid cell populations to wild-type levels. Surprisingly, deletion of Ccl5 did not rescue the gross metabolic phenotype observed in miR-146a-/- mice subjected to HCC induction, indicating that miR-146a plays an independent role in regulating HCC and metabolic disease. Taken together, this work reveals a critical host-protective role for miR-146a in HCC that is mechanistically dependent on CCL5 and wherein tumor burden correlates with two suppressive immune populations, providing an impetus for targeting these pathways to combat HCC. Furthermore, the correlations with tumor burden and Taa cells suggest that aging may increase HCC risk through the accumulation of CCL5-expressing Taa cells.

Significance: The findings in this study highlight the potential of a miRNA-based therapy in the treatment of, and as a biomarker for, liver cancer, something especially promising given the liver's avid uptake of RNA. Additionally, this work reveals possible causal roles in liver cancer for two unique immune cell types that are prevented by miR-146a.

Anti-PD1/-PDL1 therapy has attracted great attention in cancer therapy in recent years, but a serious problem remains that only a small portion of patients can benefit from it. In this study, we attempted to identify a molecule that is associated with anti-PD1/-PDL1 therapeutic efficacy through proteomic profiling of plasma obtained from patients with advanced gastric cancer (AGC) receiving anti-PD1 nivolumab monotherapy. We collected peripheral blood from 91 patients with AGC before and after nivolumab treatment, and plasma was analyzed by the SomaScan v4.1 and ELISA. Relationships between the levels and patient prognosis were statistically analyzed. To evaluate antitumor effects induced by blocking the identified molecule for which high levels were significantly associated with poor prognosis, in vivo therapeutic experiments using mouse tumor models were conducted. Proteomic data revealed that the levels of 14 molecules both before and after treatment were significantly higher in patients with progressive disease (PD) than those in non-PD patients. Among them, angiopoietin-like 3 (ANGPTL3) levels were notably higher in PD patients than those in non-PD patients, and patients with high levels of ANGPTL3 either before or after treatment showed significantly worse prognosis. In mouse tumor models with increased ANGPTL3, anti-ANGPTL3 therapy significantly reduced tumor growth and synergistically enhanced anti-PD1 therapeutic efficacy. These suggest that high levels of ANGPTL3 in plasma are a significant risk factor associated with unresponsiveness to anti-PD1 treatment and poor prognosis. Targeting ANGPTL3 in the peripheral circulation may be a promising strategy to improve clinical outcomes in anti-PD1/-PDL1 therapy for AGC.

Significance: This study provides valuable evidence suggesting the importance of targeting peripheral ANGPTL3 in the anti-PD1/-PDL1 therapy for AGC and will encourage and accelerate the development of a useful biomarker to predict responders/nonresponders to the therapy, leading to improved clinical outcomes in the treatment of gastric cancer.

Purpose: The CDK4/6 inhibitor palbociclib delays progression in patients with advanced dedifferentiated liposarcoma (DDLPS). In carcinoma models, CDK4/6 and PD-1 inhibition induce intratumoral inflammation and synergistic activity. Comprehensive assessment of tumor and host dynamics is needed to understand response and resistance to this combination.

Patients and methods: We performed a phase 2 study of palbociclib and the PD-1 inhibitor retifanlimab in advanced DDLPS. Palbociclib was administered 2 weeks prior to retifanlimab. Tumor biopsies were analyzed by single-cell RNA sequencing (scRNA-seq), and peripheral blood by high-parameter flow cytometry. Analyses focused on cell cycle, senescence, and immune-related changes.

Results: Twelve patients were treated before the study was halted because of a 42% immune-related toxicity rate. The overall response rate was 8.3%, and the disease control rate was 75%. Median progression-free and overall survival rates were 7.1 and 26.8 months, respectively. Nine patients had at least one tumor biopsy analyzed; three had paired. Ten patients had paired blood samples analyzed. Following treatment, tumor cells demonstrated decreased cycling and increased cell-cycle checkpoint activity. Transcriptional scores for senescence increased in cancer cells, as did the proportion of intratumoral T and B cells. A cluster of cells emerged with upregulated cell-cycle genes and downregulated HLA class I, suggesting innate or acquired resistance to treatment. In blood, a subset of CD4+ T cells decreased, whereas expression of LAG-3, ICOS, and CD38 increased in select subsets.

Conclusions: A palbociclib lead-in prior to retifanlimab had a high rate of immune-related toxicities. Correlative analyses identified changes in tumor and immune cells attributable to treatment. A study of concurrent dosing of the combination is ongoing.

Significance: In this phase 2 study of palbociclib and retifanlimab, treatment led to immune-related adverse events, halting enrollment. scRNA-seq and flow cytometry revealed cell-cycle suppression, senescence, and T-cell changes. These findings highlight the rationale for this combination and the need for safer dosing strategies in larger cohorts.

External auditory canal squamous cell carcinoma (EACSCC) is an exceptionally rare malignancy related to chronic tissue damage and inflammation. The molecular underpinnings of EACSCC are poorly understood, and evidence-based therapeutic strategies are not fully developed. In this study, we performed integrated multiomics analyses of RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) for Yes-associated protein (YAP) and histone 3 lysine 27 acetylation (H3K27Ac) in primary EACSCC and noncancerous ear skin samples. RNA-seq indicated hyperactivation of the YAP/TEA domain family members (TEAD)-mediated transcriptional program in EACSCC, which was significantly correlated with poor clinical outcomes. ChIP-seq suggested gained accessibility for transcription factor (TF) binding sites for TEAD, AP-1, and paired-like homeodomain (PITX) TFs in EACSCC and the presence of EACSCC-specific super-enhancers (SE). Importantly, YAP-bound SEs were involved in oncogenic transcription, including EGFR signaling. For further validations, functional experiments were performed in vitro and in vivo. The small-molecule TEAD inhibitor (smTEADi) VT104 significantly suppressed the proliferation and clonogenicity of EACSCC-derived cells. Interestingly, smTEADi not only inhibited the YAP-TEAD interaction but also induced YAP-PITX2 binding, suggesting that PITX2 could represent an alternative partner TF of YAP under TEAD-inhibited conditions in EACSCC. Knockdown of PITX2 enhanced sensitivity to VT104, inhibiting cell growth and migration of EACSCC and head and neck squamous cell carcinoma cells, whereas overexpression of PITX2 induced oncogenic gene expression programs, as well as YAP/TEAD target genes, promoting tumor growth in vivo. Of note, nuclear YAP and PITX2 were coexpressed in primary EACSCC tissues and significantly correlated with the poor prognosis of patients with EACSCC. Together, this study highlighted the hyperactivated YAP-driven transcriptional program and its potential as a therapeutic target in EACSCC.

Significance: This study provides evidence for the hyperactivation of YAP/TEAD-driven transcriptional programs in EACSCC, an exceptionally rare malignancy related to chronic tissue damage and inflammation. A comprehensive multiomics approach, including YAP and H3K27Ac ChIP-seq in clinical samples, not only suggested hyperactivation of YAP/TEAD but also identified YAP-PITX2 as a potential oncogenic transcriptional machinery under TEAD-inhibited conditions. Our results may provide a better understanding of EACSCC and contribute to the future development of therapeutic strategies.

Recent studies have reported a link between elevated B12 levels and increased incidence of malignancies. In this study, we compare the association between B12 levels and adverse outcomes in colon cancer, including metastases and mortality. A globally federated multi-institutional database identified patients with colon cancer who had at least one B12 measurement within 1 year of diagnosis. Patients were stratified by B12 status (normal: 300-1,000, elevated: >1,000, and low: <300 pg/mL). Median overall survival (mOS) was compared via log-rank test and Cox proportional hazards models. The incidence of cancer metastases and elevated liver enzymes within 1 year of diagnosis was analyzed and compared using risk ratios. Further gene expression analysis of 283 colon cancer samples from The Cancer Genome Atlas (TCGA) and 304 normal colon tissues from the Genotype-Tissue Expression (GTEx) project was performed. A total of 37,106 patients were identified by TriNetX. High B12 (n = 6,523; mOS = 59.4 months) was associated with a decreased mOS compared with normal (n = 23,965; mOS = 129.8 months) and low (n = 5,167; mOS = 137.3 months) B12 patients. Patients with elevated B12 had higher metastatic involvement and tumor stage at diagnosis and a higher 1-year incidence of all metastases, liver, lung, and peritoneal metastases [risk ratio with 95% confidence intervals of 1.30 (1.24-1.36), 1.56 (1.45-1.68), 1.43 (1.27-1.61), 1.39 (1.24-1.55), respectively]. Gene expression analysis of TCGA and GTEx identified the expression of the B12-dependent methionine synthase (MTR) to be elevated in colon cancer tissue, and increased MTR expression was associated with decreased colon cancer survival (65.8 months vs. undefined). These findings identify the potential clinical relevance of B12 as a biomarker for colon cancer metastases and survival.

Significance: Elevated B12 has been reported to be associated with increased cancer incidence; however, its role as a prognostic marker in colon cancer is unclear. In this multi-institutional study investigating clinical outcomes of patients with colon cancer, we demonstrate elevated B12 as a potential biomarker for colon cancer metastases and survival.

Cuproptosis, a regulated cell death caused by copper-dependent enzyme overactivation in the TCA cycle, leads to proteotoxic stress. While the copper chaperone ATOX1 plays a key role in cuproptosis, its link to acute myeloid leukemia (AML) progression remains unclear. In this study, elesclomol (ES) or disulfiram (DSF)/Cu was used to induce cuproptosis, and bathocuproine disulfonic acid (BCS) was used to inhibit it. An AML xenograft mouse model was also established to validate their effects in tumor tissue. Our study demonstrated that ATOX1 is downregulated in AML. Knockdown of ATOX1 promoted cell viability and proliferation, reduced the proportion of cells in the G2/M phase, and decreased cell death. In contrast, overexpression of ATOX1 produced the opposite outcomes. Moreover, ATOX1 knockdown attenuated ES/Cu-induced cuproptosis in AML cells, whereas ATOX1 overexpression enhanced it. This promoting effect of ATOX1 overexpression was effectively counteracted by the copper chelator BCS. Delving deeper, we discovered that ATOX1 is subject to m6A modification mediated by ALKBH5. Consequently, ALKBH5 can influence cuproptosis in AML cells by regulating ATOX1 expression. In vivo, the role of the ALKBH5-ATOX1 axis in AML progression has also been confirmed. In Conclusion, The demethylase ALKBH5 downregulates ATOX1 by reducing its m⁶A levels, thereby modulating cuproptosis in AML-a mechanism that offers potential novel insights and therapeutic targets for AML treatment.

Purpose: INBRX-105, a tetravalent, PD-L1-targeted TNFRSF9 (4-1BB) agonist, demonstrated preclinical antitumor activity. This first-in-human study evaluated INBRX-105 in solid tumors.

Patients and methods: This open-label, 4-part, phase 1 study evaluated INBRX-105 alone or with pembrolizumab in adults with locally advanced/metastatic, unresectable solid tumors (NCT03809624). INBRX-105 was administered intravenously Q2W or Q4W in parts 1 (single-agent dose escalation; 0.001-3.0 mg/kg) and 2 (single-agent expansion) or Q3W in parts 3 (combination dose escalation; INBRX-105 0.03-1.0 mg/kg) and 4 (combination expansion). Part 2 enrolled patients with checkpoint inhibitor-relapsed/refractory (CPI-R/R) tumors. Part 4 enrolled patients with CPI-R/R or CPI-naive disease. The primary endpoint was safety and tolerability of INBRX-105. Preliminary clinical response was a secondary endpoint.

Results: Of 160 patients assessed, 81 received monotherapy (median age, 65.0 years; female, 50.6%), and 79 combination therapy (median age, 64.0 years; female, 38.0%). The INBRX-105 maximum tolerated dose was 0.3 mg/kg Q3W. Head and neck squamous cell carcinoma (n=61) and non-small cell lung cancer (n=25) were the most common tumor types. The most common any-grade INBRX-105-related adverse events (AEs) were fatigue (monotherapy, 35.8%; combination, 17.7%), increased aspartate aminotransferase (25.9%; 15.2%), and nausea (19.8%; 17.7%). INBRX-105-related hepatic AEs occurred in 41 patients (monotherapy, n=25 [grade ≥3, n=11]; combination, n=16 [grade ≥3, n=6]). In all patients, the objective response rate was 8.8% (monotherapy, 3.7%; combination, 13.9% [CPI naive, 30.0%; CPI R/R, 8.6%]); disease control rate was 43.1%.

Conclusions: The low response rates and hepatic safety signals observed do not support further clinical development of INBRX-105.

The microRNA miR-146a regulates several aspects of chronic inflammation, including the hepatocellular carcinoma (HCC) risk factor, steatohepatitis. Here, we find that loss of miR-146a leads to significantly increased tumor burden over a 9-month timeframe in a mouse model of HCC. Notably, this miR-146a-/- phenotype is most pronounced in females, who are typically not sensitive to this model. Mechanistically, we identified increases in dysfunctional CD8+ T cells that express high levels of CCL5 and resemble Age-Associated T (Taa) cells, as well as elevated levels of myeloid cells with a myeloid-derived suppressor cell (MDSC) phenotype, a class of myeloid cells that suppresses tumor immunity. Deletion of Ccl5 from miR-146a-deficient mice returned tumor growth and the aberrant myeloid cell populations to wild-type (WT) levels. Surprisingly, deletion of Ccl5 did not rescue the gross metabolic phenotype observed in miR-146a-/- mice subjected to HCC induction, indicating that miR-146a plays an independent role in regulating HCC and metabolic disease. Taken together, this work reveals a critical host-protective role for miR-146a in HCC that is mechanistically dependent on CCL5 and wherein tumor burden correlates with two suppressive immune populations, providing an impetus for targeting these pathways to combat HCC. Further, the correlations with tumor burden and Taa cells suggest that aging may increase HCC risk through the accumulation of CCL5-expressing Taa cells.