Cancer Science最新文献

The BRAF V600E mutation is observed in 2% of the patients with lung adenocarcinoma (LUAD), and combination therapy targeting BRAF and mitogen-activated protein kinase (MEK) is the standard treatment for this population. However, acquired resistance inevitably develops, which highlights the need for novel therapeutic strategies. In this study, we established a patient-derived BRAF V600E-mutated LUAD cell line, KTOR81, and investigated the potential of targeting the Yes-associated protein 1 (YAP1)/transcriptional enhanced associate domain 1 (TEAD1) pathway in combination with BRAF inhibition. We observed that the novel TEAD1 inhibitor VT103 enhanced the efficacy of the BRAF inhibitor dabrafenib in KTOR81 cells and xenograft models. The combination of dabrafenib and VT103 downregulated the expression of the antiapoptotic protein survivin, which is transcriptionally regulated by the YAP1/TEAD1 complex, leading to increased apoptosis. Moreover, we used a LUAD tissue microarray to compare the staining patterns of YAP1, TEAD1, and survivin, and examined their association with prognosis. These analyses revealed a strong correlation between YAP1, TEAD1, and survivin expression in LUAD, suggesting the relevance of the YAP1/TEAD1-survivin axis beyond BRAF V600E-mutated cases. While no statistically significant association was observed between survivin expression and prognosis, when limited to driver oncogene-positive patients, high survivin expression was suggested to be associated with poor prognosis. These findings provide preclinical evidence for the efficacy of combining TEAD1 inhibition with BRAF-targeted therapy in BRAF V600E-mutated LUAD and highlight the YAP1/TEAD1-survivin axis as a potential therapeutic target especially in the driver oncogene-positive LUAD patients.

Homologous recombination deficiency (HRD) tests, including MyChoice CDx, are companion diagnostics for poly (ADP-ribose) polymerase (PARP) inhibitors. BRCA1 promoter hypermethylation, a major HRD cause, may correlate with poorer prognosis. This study aimed to develop a simple, accurate method for detecting BRCA1 promoter hypermethylation and elucidate the characteristics of such cases. BRCA1 promoter methylation was analyzed using bisulfite sequencing (BIS-seq) in high-grade serous ovarian carcinoma specimens. We developed a newly developed BRCA1 methylation assay, BRCA1-Fragment Analysis of Methylation (BRCA1-FAM), which combines restriction enzyme digestion with fragment analysis. The accuracy of this assay was compared to the results of BIS-seq. We evaluated the relationship between BRCA1 promoter hypermethylation and prognosis and examined its association with BRCA1 expression and loss of heterozygosity. BRCA1 mutations and promoter methylation were mutually exclusive in the analyzed cases, with methylation observed in 28.9% (22/76) of primary debulking surgery cases. The BRCA1-FAM showed high sensitivity (91.3%) and specificity (100%) for detecting BRCA1 promoter hypermethylation, comparable to BIS-seq. Cases with BRCA1 promoter hypermethylation had significantly poorer progression-free survival (log-rank test, p = 0.048). Among these cases, 86.4% displayed abnormal BRCA1 immunostaining, with lower frequencies of BRCA1 loss of heterozygosity compared to those of other groups. BRCA1 promoter hypermethylation is associated with poor prognosis, underscoring the importance of its identification for HRD stratification. BRCA1-FAM is a simple and highly accurate method for evaluating BRCA1 promoter methylation. This approach may potentially enhance the precision of personalized therapies for ovarian cancer.

T-cell lymphoma (TCL) poses a significant challenge in clinical oncology, characterized by its aggressive behavior and resistance to conventional therapies. Despite considerable research efforts, the prognosis for TCL patients remains poor, primarily due to the lack of effective therapeutic strategies that can inhibit tumor progression and metastasis. In this study, we identified CaMKII-α as a potential therapeutic target for TCL. To explore its role in TCL pathogenesis, we investigated its effects on TCL cell lines. Protein expression levels within the PI3K-AKT signaling pathway were assessed using western blot analysis. Through siRNA-mediated gene silencing, we downregulated CaMKII-α expression and monitored TCL cell proliferation. Furthermore, we identified Evans Blue (IC₅₀ = 197.1 nM) as a selective small-molecule inhibitor of CaMKII-α through high-throughput screening (HTS). Evans Blue demonstrated significant tumor-suppressive effects, potentially inhibiting TCL cell proliferation via regulation of the PI3K-AKT signaling pathway. Notably, the antitumor effect of Evans Blue was comparable to that observed with genetic CaMKII-α ablation, highlighting its potential as a novel therapeutic strategy for the treatment of TCL.

Long noncoding RNAs (lncRNAs), a class of noncoding RNAs exceeding 200 nucleotides in length, play critical roles in regulating diverse biological processes and gene expression. Emerging evidence highlights their significant association with cancer occurrence, progression, prognosis, and therapeutic resistance, positioning lncRNAs as promising molecular targets for tumor detection and treatment. Ferroptosis, a regulated form of cell death characterized by the accumulation of iron-dependent lipid peroxides, has gained attention as a potential therapeutic strategy for cancer, complementing existing modalities such as surgery, chemotherapy, radiotherapy, hormone therapy, and targeted molecular therapy. Recent research demonstrates that lncRNAs modulate ferroptosis in solid tumors, thereby influencing tumor cell invasion, metastasis, and proliferation. Inducing ferroptosis has been shown to inhibit tumor growth, reduce chemoresistance, and enhance radiotherapy efficacy. This review explores recent advancements in understanding the role of lncRNAs in tumor ferroptosis, with a focus on their involvement in iron metabolism and their potential as therapeutic targets in cancer combination therapies.

In Japan, cancer control measures have been developed in specialized hospitals for children (0-14 years), and adolescents and young adults (15-39 years) patients with cancer. We investigated geographical discrepancies between residential addresses and cancer treatment hospitals in patients aged 0-39 in Japan between 2016 and 2019. Using Japan's National Population-Based Cancer Registry data (n = 99,968), we classified the cases into 10 diagnostic groups and four age groups: 0-14, 15-19, 20-29, and 30-39. Using five types of hospital groups, we examined the origin-destination relationships between patients' residences and hospitals at the prefecture and Secondary Medical Area (SMA) levels via cross-tabulation, summarizing the results using descriptive statistics and heat maps. Generalized Estimating Equation analysis was performed to investigate the factors associated with receiving treatment outside the residential prefecture based on individual data. The median percentage of patients receiving treatment within their residential prefecture was 81.82% or higher across age groups and hospital groups. At the SMA level, the percentage ranged from 0% to 57.00% (median)-minimum 0.0% and maximum 100.0%. Model analysis revealed that patients with retinoblastoma (adjusted risk ratio: 5.45) and those living in metropolitan (Tokyo: 3.73, Osaka: 2.00) and non-metropolitan and depopulated (1.67) areas were significantly more likely to travel outside their residential prefectures. These findings reveal that Japan faces geographical discrepancies in access to cancer care, particularly for specific cancer types and areas. These findings can inform targeted interventions to support equitable access to specialized cancer care for young Japanese patients.

Heat shock protein 90 (HSP90) plays a crucial role in the maintenance of protein homeostasis in cancer cells. Inhibition of HSP90 is anticipated to exert anticancer activities by reducing levels of HSP90 client proteins. Pimitespib (TAS-116) has emerged as a potent ATP-competitive inhibitor of both HSP90α and β, demonstrating favorable therapeutic properties in preclinical models. Notably, pimitespib is the first HSP90 inhibitor approved for the treatment of advanced gastrointestinal stromal tumors in Japan. Poly(ADP-ribose) polymerase (PARP) inhibitors target cancers susceptible to the homologous recombination (HR) pathway and are used for treating various types of tumors, particularly those harboring defects in HR repair pathways within DNA damage repair (DDR) such as mutations in breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively). However, PARP inhibitors have shown limited efficacy in HR-proficient tumors, and the development of resistance to PARP inhibitors via restoration of DDR systems poses a significant challenge. In this study, we explored the potential of pimitespib to enhance PARP inhibitor activity. In PARP inhibitor-insensitive breast cancer cell lines, pimitespib impaired HR pathway function by promoting the proteasome-mediated degradation of proteins involved in HR, such as BRCA1, BRCA2, and Rad51 homologous 1 (RAD51). Consequently, pimitespib enhanced antitumor activity and DNA damage induced by PARP inhibitors in vitro. In human breast cancer xenograft mouse models, pimitespib downregulated RAD51 proteins and augmented the antitumor effects of PARP inhibitors. These findings highlight the potential of pimitespib as a therapeutic agent in combination with PARP inhibitors to treat PARP inhibitor-insensitive cancers.

While male breast cancer (MBC) remains a rare and understudied disease, comparatively little is known about its prognosis in contrast to female breast cancer (FBC). There is a paucity of large population-based studies comparing the prognosis of MBC patients to FBC patients in Japan. This study analyzed 181,540 breast cancer cases, 1058 (0.6%) males and 180,482 (99.4%) females, from 12 prefectures in Japan diagnosed between 1993 and 2011. Five- and ten-year net survival (NS) were estimated and stratified by sex, period, age, stage, and histological groups. Excess hazard ratios (EHR) were adjusted for period, age, stage, and histological group. Cochran's Q test was utilized to assess heterogeneity across these factors. The overall 5- and 10-year NS estimates for MBC patients were 90.7% (95% CI: 86.3%-93.7%) and 83.7% (95% CI: 72.2%-90.8%), respectively, while those for FBC patients were 88.3% (95% CI: 88.1%-88.5%) and 79.1% (95% CI: 78.7%-79.4%), respectively. The survival of MBC patients was comparable to that of FBC patients, with EHR of 0.88 [95% CI: 0.70-1.09] and 0.86 [95% CI: 0.69-1.07] for 5- and 10-year survival, respectively. Heterogeneity analysis revealed no significant sex-based differences in survival across these strata. This study offers a comprehensive analysis of breast cancer survival in Japanese men and women and enhances understanding of MBC prognosis relative to FBC.

The Aurora-A kinase inhibitor MLN8237 has shown efficacy in clinical trials for advanced breast cancer; however, its use as a monotherapy is limited by significant side effects and modest efficacy. Therefore, combining MLN8237 with other agents at lower doses may provide a viable alternative. In this study, we evaluated the combination of MLN8237 with the BH3 mimetic ABT263 for the treatment of triple-negative breast cancer (TNBC). We found that this combination significantly suppressed tumor growth and metastasis in immunocompetent syngeneic mouse models, whereas its efficacy was attenuated in immunodeficient xenograft models. Mechanistic studies revealed that the combination enhanced anti-tumor immunity by increasing the presence of CD8⁺ T cells and NK cells, while reducing the number of immunosuppressive cells in the tumor microenvironment. This shift resulted in elevated levels of IFN-γ and granzyme B, which activated the extrinsic apoptotic pathways in cancer cells. Notably, the combination treatment did not affect tumor cell proliferation but promoted apoptosis with minimal toxicity. Furthermore, the synergistic effect of MLN8237 and ABT263 in inducing intrinsic apoptosis was primarily driven by the inhibition of the AKT-Mcl-1 and Bcl-xL survival pathways in cultured tumor cells. Together, these findings support the MLN8237-ABT263 combination as an effective treatment strategy for TNBC, promoting both immune-mediated extrinsic apoptosis and inactivation of Bcl-xL/Mcl-1-dependent intrinsic anti-apoptotic pathways.