Cancer Science最新文献

Redox regulation is a key mechanism supporting tumor survival and an attractive therapeutic target. In this study, we screened 1161 FDA-approved compounds to identify agents that induce reactive oxygen species (ROS) accumulation in head and neck squamous cell carcinoma (HNSCC) cells. Pimozide, a dopamine D2 receptor antagonist, emerged as the most potent ROS inducer. It selectively suppresses the growth of HNSCC cells with high oxidative stress resistance while exhibiting only modest effects on less resistant cells and normal keratinocytes. Notably, pimozide exhibited anti-tumor effects as a monotherapy and in combination with paclitaxel at clinically relevant doses. Mechanistic analysis revealed that pimozide rapidly induced ROS accumulation via a mechanism distinct from its known action on dopamine D2 receptors and STAT3/5. To identify markers of ROS-induced responses, we examined ROS-responsive genes and found that early growth response 1 (EGR1) was selectively induced in sensitive cells and correlated with pimozide responsiveness. Functional analysis revealed that EGR1 knockdown suppressed pimozide-induced cytotoxicity, suggesting its role as a functional pharmacodynamic marker of pimozide sensitivity. In a patient-derived xenograft model of HNSCC, pimozide significantly reduced the tumor burden alone and in combination with paclitaxel. While tumor volume reduction in the combination group was not statistically greater than that in the monotherapy group, fluorescence immunohistochemistry revealed a marked decrease in undifferentiated tumor cells, indicating enhanced therapeutic effects of combination treatment. Taken together, these findings indicate that pimozide is a promising candidate for repurposing as a novel therapeutic agent against HNSCC.

Unmet challenges in systemic therapy persist for advanced renal cell carcinoma (RCC) despite the widespread use of anti-angiogenetic tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). We previously showed that dipeptidyl peptidase 4 inhibitor (DPP4i) improved TKI sensitivity using patient-derived RCC cells and experimental TKI-resistant models. To address whether DPP4i is clinically useful for the enhancement of RCC systemic therapy, including ICIs, we analyzed 320 cases with RCC who underwent systemic therapy. Patients with DPP4i treatment exhibited longer overall survival (hazard ratio: 0.50, 95% confidence interval: 0.30–0.82, p = 0.0060). In the Cox proportional hazards model, the use of DPP4is, along with BMI ≥ 25, no metastasis, low serum lactate dehydrogenase (LDH), and low serum C-reactive protein (CRP), was a favorable prognostic factor. Additionally, more pronounced tumor shrinkage was observed in a within-subgroup comparison of patients receiving TKI or ICI as first-line therapies. Consistently, we found that DPP4 high RCC tumors exhibit reduced immune infiltration and lower scores for effector T cell infiltration-related signatures based on the RNA sequencing data from the CheckMate-009, 010, and 025 studies. These findings can potentially change the interpretation of the prognostic impact of type 2 diabetes mellitus on RCC and bolster the rationale for initiating a prospective clinical trial to evaluate concurrent use of DPP4i with RCC therapeutic strategies.

Wang H, Jiang X, Cheng Y, et al. MZT2A promotes NSCLC viability and invasion by increasing Akt phosphorylation via the MOZART2 domain. Cancer Sci. 2021;112:2210–2222. https://doi.org/10.1111/cas.14900

In the above article, Figure 3E is incorrect. The correct image is shown below:

We apologize for this error.

Tumor suppressor p53 is the most frequently mutated gene in cancers. Mutations in p53 not only result in the loss of its classical tumor-suppressive functions but also confer new oncogenic properties. The protein stabilization of mutant p53 (mutp53) is a prerequisite for gain-of-function manifestation. Here, we report the novel mechanism that pyruvate dehydrogenase kinase1 (PDK1) modulates both wild-type and mutant p53, and facilitates proliferation and migration of TP53 mutant breast cancer. On the one hand, we identified PDK1 as a direct transcriptional repression target of wild-type p53, whereas transcriptional activation of PDK1 in mutp53 cells is initiated by the EGR1 axis. On the other hand, PDK1 promoted mutp53 protein accumulation by binding to mutp53 and inhibiting its degradation. Taken together, mutp53 activated a positive feedback loop by upregulating PDK1 to enhance p53 protein stability and promote the malignancy of breast cancer. Moreover, PDK1 inhibition increased the therapeutic effect of APR-246 on TP53 mutant breast cancer in xenograft tumors. Our results suggested that intervention of PDK1 could potentially emerge as a new therapeutic strategy to impede the progression of TP53 mutant breast cancer.

To develop an optimized genomic medicine platform for pediatric cancers, a nationwide cancer genome profiling project was conducted from January 2022 to February 2023 in collaboration with the Japan Children's Cancer Group. This prospective observational study analyzed matched blood and FFPE tumor samples from patients aged 0–29 years with solid tumors. Genomic analysis used the TOP2 hybrid capture–enrichment system, targeting 737 and 455 genes in the DNA and RNA panels, along with allele-specific genome copy number alterations. A total of 210 patients from 50 institutions were enrolled across Japan (median age, 8 years; range, 0–25). Of these, 154 (77%) were enrolled at diagnosis or during/after initial treatment and 56 (27%) at disease progression or relapse. The TOP2 findings had great benefits in clarifying the diagnosis of pediatric solid tumors. Among the 204 patients with genomic results, 147 (72%) had potentially actionable findings, including diagnostic, prognostic, and therapeutic findings in 111 (54%), 61 (30%), and 64 (31%), respectively. Oncogenic fusions were noted in 45 (23%) patients. A copy number alteration was identified in at least one genomic region in 170 (83%) patients. Two patients exhibited a high tumor mutation burden. Seventeen (8%) patients harbored a germline pathogenic/likely pathogenic variant in cancer-predisposing genes. This study highlighted the feasibility of implementing a nationwide precision medicine platform and the clinical utility of the TOP2 system for pediatric cancers. The results support the integration of genomic data into the standard clinical care of pediatric patients with cancer, both at diagnosis and at relapse.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive and refractory hematologic malignancy that is caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. ATL results from a combination of viral latency and the accumulation of abnormalities throughout the genome, epigenome, transcriptome, and signaling pathways. Despite numerous studies, the data have been largely fragmentary, and a comprehensive understanding of this disease remains unclear. Recent comprehensive analyses have contributed not only to the identification of fundamental molecular abnormalities in ATL, but also to the development of novel therapeutic strategies and prognostic models. In this review, an overview of the latest advances in the genomic, epigenomic, and transcriptomic alterations associated with ATL is provided, which highlights the opportunities for clinical management of ATL. Integrated omics approaches will further increase our understanding of refractory disease and provide a foundation for designing new treatments that target core molecular drivers.

Histone deacetylase inhibitors, such as vorinostat, show promise as treatment for T-cell lymphomas including cutaneous T-cell lymphoma. However, the emergence of resistance ultimately leads to disease relapse. To elucidate the underlying mechanisms and identify potential countermeasures, we established histone deacetylase inhibitor-resistant cutaneous T-cell lymphoma cell lines by prolonged exposure to vorinostat. We then comprehensively profiled gene expression in these cell lines by using microarrays and in silico analytical approaches. We identified 83 genes that were significantly upregulated in the resistant cell lines. Subsequent enrichment analyses using ChIP-Atlas and Enrichr revealed that these genes are regulated by particular transcription factors, including RELA/p65, GATA3, and EP300, of which RELA (p65) exhibited the highest composite score. RELA is a key subunit of the NF-κB complex, which is involved in inflammation, cell survival, and proliferation. We demonstrated marked upregulation and nuclear enrichment of p65 and pronounced NF-κB pathway activation in the histone deacetylase inhibitor-resistant cells. The mechanism involved acetylation-mediated inhibition of p65 ubiquitination, which resulted in protein stabilization and enhanced transcriptional activity. Histone deacetylase inhibitor-resistant cell lines displayed heightened sensitivity to inhibition of the NF-κB pathway by bortezomib and dimethyl fumarate. These findings implicate aberrant NF-κB activation as a central driver of the emergence of histone deacetylase inhibitor resistance in cutaneous T-cell lymphoma. Ultimately, our results provide a strong rationale for exploring NF-κB inhibition as a therapeutic strategy to restore or enhance the efficacy of histone deacetylase inhibitor-based therapies, overcome histone deacetylase inhibitor resistance, and improve outcomes for patients with cutaneous T-cell lymphoma.

Despite recent advancements in multimodal therapies for esophageal squamous cell cancer (ESCC), the prognosis remains poor. Identifying suitable biomarkers for predicting prognosis and exploring new therapeutic targets are essential to improving treatment outcomes in ESCC. In this study, we utilized proteomic technology to identify the transferrin receptor (TfR), the main cellular iron importer, as a novel tumor antigen in ESCC. The clinicopathological characteristics of TfR were evaluated by immunohistochemistry using ESCC specimens, revealing that high TfR expression was associated with poor prognosis. Knockdown of TfR in ESCC cell lines resulted in a decrease in intracellular iron levels and suppressed the proliferation of ESCC cell lines, inducing cell cycle arrest in the G0/G1 phase by inhibiting cyclin D, cyclin E, and cyclin-dependent kinase 2. Furthermore, the administration of deferoxamine (DFO), an oral iron chelator, induced a decrease in intracellular iron and suppressed the proliferation of ESCC cell lines and an increase in caspase 3 and 7 activity, indicating the induction of apoptosis. In an ESCC xenograft mouse model, the DFO-treated group exhibited decreased serum iron levels and reduced tumor size. Finally, we confirmed that the deficiency of iron in ESCC cell lines induced an increase in TfR expression via upregulation of iron regulatory protein 2. These findings suggest that TfR is an independent prognostic factor in ESCC and that targeting iron metabolism may be a promising therapeutic approach for improving ESCC treatment outcomes.

Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses of all cancer types. Immune checkpoint inhibitors (ICIs) are currently not indicated for patients with PDAC except for those with high microsatellite instability. In this study, we developed an immunocompetent orthotopic transplant mouse model with Kras and Trp53 mutations, characterized by high fibrosis and an immunosuppressive tumor microenvironment, closely mimicking human PDAC lesions. This model provides a robust platform for investigating strategies for improving ICI efficacy. We observed that ICI monotherapy yielded minimal efficacy, whereas anti-CD40 agonist antibody (aCD40) monotherapy prolonged survival despite its low impact on primary tumor volume. Moreover, ICIs + aCD40 combination therapy not only extended survival but also significantly reduced tumor burden. These effects were accompanied by enhanced dendritic cell migration to the lymph nodes and T cell priming and activation. Moreover, the expression of immunosuppressive markers in tumor-associated macrophages was decreased. Indeed, gene expression analyses of infiltrating immune cells have revealed a shift in the tumor microenvironment from an immune-tolerant state to an immune-activated state. Our findings suggest that combination therapy with ICIs and aCD40 is a promising treatment strategy for patients with PDAC.

Follicular thyroid carcinoma is generally associated with a favorable prognosis; however, a subset of follicular thyroid carcinoma shows poor prognosis and frequent distant metastases, and this subset is referred to as high-risk follicular thyroid carcinoma. Difficulty in distinguishing high-risk from low-risk follicular thyroid carcinoma based on current diagnostic approaches leads to the overtreatment of patients with indolent disease. Therefore, the identification of novel biomarkers capable of reliably distinguishing high-risk follicular thyroid carcinoma is essential for accurate risk stratification. Such biomarkers may serve as therapeutic targets for metastatic follicular thyroid carcinoma. This study aimed to identify novel prognostic markers and therapeutic targets for high-risk follicular thyroid carcinoma. In this study, we conducted bulk ribonucleic acid sequencing of high-risk follicular thyroid carcinoma, including widely invasive subtypes and metastatic tumors, and we identified carbonic anhydrase 12 as a candidate biomarker. Immunohistochemical analysis revealed significantly higher carbonic anhydrase 12 expression in follicular thyroid carcinoma than in benign follicular adenomas, particularly in widely invasive and encapsulated angioinvasive subtypes. High carbonic anhydrase 12 expression was an independent predictor of poor disease-free survival, surpassing conventional clinicopathological parameters. Functional assays showed that carbonic anhydrase 12 promoted follicular thyroid carcinoma proliferation, invasion, and migration partly by regulating matrix metalloproteinase 2 expression. Furthermore, carbonic anhydrase 12 inhibitor U104 suppressed follicular thyroid carcinoma cell growth in a dose-dependent manner, and its combination with lenvatinib exerted synergistic antiproliferative effects. Collectively, these findings identified carbonic anhydrase 12 as a novel prognostic biomarker of follicular thyroid carcinoma and a promising therapeutic target.