Translational cancer research最新文献

Background and objective: Advances in non-clear cell renal cell carcinoma (RCC) have lagged behind clear cell RCC due to the heterogeneity and relative rarity of the disease. However, more advanced molecular and genetic testing has allowed us to gain a more detailed and nuanced appreciation of these malignancies. This has laid the foundation for the identification of the distinct mutational and molecular patterns such as succinate dehydrogenase (SDH)-deficient RCC, fumarate hydratase (FH)-deficient RCC, and translocation RCC, so that clinicians can create a more personalized approach to their clinical management. Particularly for the rare non-papillary RCC variant histologies, clinical trial representation is lacking. In the discussed studies, no histology enrolled more than 29 patients of any particular RCC aside from Papillary. As such, evidence-based management decisions can be challenging to make for this patient population.

Methods: We have collected the most up-to-date available evidence to describe the pathophysiology, molecular, and pathologic characteristics of the more commonly seen non-clear cell RCC variants, including papillary, chromophobe, translocation, FH-deficient, as well as a group of "unclassified" RCCs. Additionally, we provide an overview of the available evidence from recent clinical trials for non-clear cell RCC and current treatment paradigms.

Key content and findings: The diagnostic approach for renal malignancies is rapidly changing, favoring a more molecular and genetically based approach. These techniques will allow for a more detailed understanding of the clinical behavior of these cancers. Most data for non-clear cell RCC are from single-arm phase 2 clinical trials. The clinical response to vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) varies greatly by histology.

Conclusions: Molecularly targeted therapy as monotherapy or when combined with immunotherapy have efficacy in non-clear cell RCC, though there are differences in treatment response by histology.

Background: Treating patients with head and neck adenoid cystic carcinoma (HNACC) presents surgical problems in various scenarios. Limited studies explore definitive radiation's impact on patient survival, with inadequate data correlating it to postoperative radiotherapy. Using the Surveillance, Epidemiology, and End Results (SEER) program, we conducted an objective analysis to evaluate the impact of definitive radiation on the survival of HNACC patients without distant metastases, aiming to uncover its nuanced pros and cons.

Methods: This study conducted a comprehensive analysis of individuals diagnosed with HNACC within the SEER database from 2000 to 2023. Disease-specific survival (DSS) and overall survival (OS) were evaluated using diverse statistical methods. Propensity score matching (PSM) reduced covariate variations and selection biases, allowing for comparisons of postoperative and definitive radiotherapy groups.

Results: A total of 2,072 patients were encompassed within this study. The postoperative radiotherapy group yielded significant advantages in OS and DSS (P<0.001). In matched cohorts, the 5-year prognostic OS stood at 55% and 37%, respectively, while DSS figures were 65% and 46%, correspondingly. In advanced T4 cases, DSS differences lacked significance (P=0.42). Additionally, the outcomes of OS and DSS were notably influenced by variables such as T-stage, N-stage, tumor stage, and chemotherapy.

Conclusions: Surgical intervention remains a pivotal component of comprehensive treatment for patients diagnosed with operable HNACC. Definitive radiation is appropriate for less treatable situations, particularly in local advanced HNACC. Systemic treatment may assist HNACC patients at risk of distant metastases.

Background: Ovarian cancer (OC) is a highly aggressive and often fatal disease that frequently goes undetected until it has already metastasized. The classic treatment for OC involves surgery followed by chemotherapy. However, despite the effectiveness of surgery, relapse is still a common occurrence. Unfortunately, there is currently no ideal predictive model for the progression and drug sensitivity of postoperative OC patients. Cell death patterns play an important role in tumor progression. So we aimed to investigate their potential to be used as indicators of postoperative OC prognosis and drug sensitivity.

Methods: A total of 12 programmed cell death (PCD) patterns were employed to construct novel classification and prognosis model. Bulk transcriptome, genomics, and clinical information were collected from The Cancer Genome Atlas (TCGA) Program-OV, GSE9891, GSE26712, GSE49997 and GSE63885. In addition, single-cell transcriptome data GSE210347 were procured from the Gene Expression Omnibus (GEO) database for subsequent analysis.

Results: In this study, a novel PCD classification has been employed to phenotype postoperative OC patients, revealing that patients in cluster 1 exhibited heightened sensitivity to immune-based therapies combined with high expression of chemokines, interleukins, interferons, and checkpoints. Meanwhile, a programmed cell death index (PCDI) was established using an 8-gene signature with the help of a machine learning algorithm. The patients with high-PCDI had a worse prognosis after surgery in OC. In addition, we also found that patients with low PCDI patients may exhibit sensitivity to immunotherapy, while those with high PCDI patients may display increased responsiveness to tyrosine kinase inhibitors.

Conclusions: This study provides a novel PCD model and nomogram that can effectively predict the clinical prognosis and drug sensitivity of OC patients post-surgery.

Background: Disulfidptosis is a novel form of cell death triggered by disulfide stress that may have important implications for breast cancer (BC) pathogenesis. Nevertheless, studies identifying disulfidptosis-associated long non-coding RNAs (lncRNAs) in BC have not been reported. This study aimed to investigate the prognostic potential of disulfidptosis-related lncRNAs in BC.

Methods: RNA-sequencing data and clinical information of BC patients were obtained from The Cancer Genome Atlas (TCGA) database. The lncRNAs associated with disulfidptosis were identified through co-expression analysis. Subsequently, a risk signature consisting of 10 lncRNAs was constructed using univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses, and its predictive power was validated.

Results: The risk signature was found to be an independent prognostic factor for BC patients. Notably, the two subgroups defined by the risk signature exhibited different mutant gene profiles, and risk scores were significantly correlated with tumor mutation burden (TMB). Additionally, single-sample gene set enrichment analysis (ssGSEA) and immune checkpoint analyses indicated that the predicted trait was significantly associated with the immune status of BC patients. Furthermore, 55 potential anticancer drugs were identified that were associated with the signature.

Conclusions: In this study, we successfully developed a prognostic model based on disulfidptosis-related lncRNAs, which enhances the accuracy of predicting the prognosis of BC patients. This model also offers a potential target and theoretical foundation for BC treatment, laying a robust groundwork for future research on the functional roles of disulfidptosis-associated lncRNAs in BC.

Background: The catenin delta 2 (CTNND2) gene has been implicated in the progression of various cancers, but its specific role in melanoma has not yet been thoroughly investigated. This study sought to explore the expression and biological function of CTNND2 in malignant melanoma tissues to identify new targets or biomarkers for melanoma diagnosis and treatment.

Methods: Immunohistochemistry was used to examine the levels of CTNND2 in melanoma and adjacent non-tumor tissues. A Western blot analysis was performed to quantify the expression levels of CTNND2 in human immortalized keratinocytes and melanoma cell lines. The Cell Counting Kit-8 (CCK-8) assay, plate colony formation assay, cell adhesion assay, scratch test, and Transwell assay were used to assess the effects of CTNND2 knockdown on the proliferation, adhesion, migration, and invasion of melanoma cells. The Harmonizome database was used to research the biological processes (BPs) involved in CTNND2.

Results: In the melanoma tissues, CTNND2 expression was substantially upregulated and its levels were closely linked with the pathological features of patients. The CTNND2 levels were notably more increased in the melanoma cell lines than the immortalized keratinocytes. The suppression of the CTNND2 gene substantially impeded the capacity of the melanoma cells to proliferate, migrate, and invade, and also significantly decreased their potential to attach to collagen I and IV, and fibronectin. The Harmonizome database results revealed a strong correlation between the BPs controlled by CTNND2 and the focal adhesion signaling pathway of the cells. The inhibition of the CTNND2 gene in melanoma cells resulted in a significant decrease in the phosphorylation of focal adhesion kinase (FAK) and the production of paxillin protein. In the melanoma cells, the reduction of CTNND2 did not have a significant effect on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. However, it did considerably prevent the activation of mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) and its downstream molecule extracellular signal-regulated protein kinase 1/2 (ERK1/2).

Conclusions: The expression of the CTNND2 gene is increased in melanoma tissues, which enhances the ability of melanoma cells to proliferate both in vivo and in vitro. Additionally, the CTNND2 gene is crucial in controlling the adhesion process of melanoma cells. This mechanism is associated with the regulation of the FAK and MEK1/2/ERK1/2 signaling pathways. Based on our findings, CTNND2 could be used as an oncogene target for melanoma and a new treatment target or diagnostic biomarker.

Background: High incidence and mortality rates underscore lung cancer as a significant global health issue. Understanding the molecular mechanisms driving its progression is crucial for developing effective treatments. This study explores a potential molecular regulator that may contribute to the progression of non-small cell lung cancer (NSCLC) by utilizing bioinformatics analyses and laboratory experiments, aiming to provide insights that could inform future therapeutic strategies.

Methods: Our research combined single-cell RNA sequencing (scRNA-seq) data analysis with the Mendelian randomization (MR) algorithm. MR analysis using genetic variants associated with NSCLC risk aimed to uncover causal relationships between genes and cancer traits. To validate the impact of neuroepithelial cell transforming 1 (NET1) on cellular proliferation and its role in inhibiting ferroptosis, we utilized quantitative real-time polymerase chain reaction (qRT-PCR), cell viability assays, and malondialdehyde (MDA) detection. Furthermore, molecular docking analyses of four compounds demonstrated their potential in modulating the downregulation of NET1.

Results: ScRNA-seq exposed cellular diversity in non-malignant lungs and tumors. Distinct expression patterns in epithelial cells and identified gene pathways pointed to cell proliferation. NET1, causally linked to NSCLC through MR analysis, showed increased expression in tumors and correlated with unfavorable overall survival, validated by functional assays. Utilizing cell viability assays and MDA detection, our results validated the pivotal role of NET1 in enhancing cellular proliferation and its efficacy in inhibiting ferroptosis. Doxorubicin, piroxicam, and quercetin emerged as potential drug candidates for NSCLC treatment based on molecular docking analysis.

Conclusions: Our findings confirm NET1's significant role in NSCLC progression, influencing cell proliferation, ferroptosis, immune activity regulation and identify potential therapeutics for targeted lung cancer treatment.

Background and objective: A standard of care for muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). Given recent improvements in NAC and the morbidity associated with RC, bladder-sparing therapy has been investigated as a promising treatment for patients with MIBC who experience a complete clinical response (CCR) to systemic therapy. However, clinical staging is unreliable, making it challenging to determine ideal candidates for bladder-sparing therapy. Our primary objective is to review the efficacy of NAC, strategies for determining a CCR as a surrogate for a complete pathologic response, and the emerging role of imaging, tumor genomics, and biomarkers in selecting candidates for bladder-sparing therapy.

Methods: We surveyed the literature for studies investigating the outcomes of current treatment modalities for MIBC and methods for determining a CCR following systemic therapy as well as the impact this has on pathologic staging. Studies employing imaging, tumor biomarkers, and genomics were included.

Key content and findings: Clinical staging with cystoscopy or transurethral resection shows significant discordance with final pathology, with high rates of understaging. Multiparametric magnetic resonance imaging (mpMRI) has shown strong utility in determining the presence of MIBC, but it has yet to reliably identify CCR. Meanwhile, somatic DNA damage repair mutations and biomarkers such as circulating and urinary tumor DNA are strong predictors of recurrence, showing promise in predicting and monitoring a CCR to systemic therapy. Multiple ongoing trials are currently assessing the use of biomarkers and genomic analyses in determining eligibility for bladder-sparing therapy.

Conclusions: While no one method has reliably demonstrated the ability to detect a true CCR, a multimodal approach involving imaging, biomarkers, and genomic analyses holds promise. We eagerly await the results of clinical trials investigating these tools, which may allow for the safe recommendation of bladder-sparing therapy.

Background and objective: The role of focal therapy in the treatment of localized prostate cancer is evolving. However, despite accumulating evidence, current guidelines and regulatory bodies refrain from endorsing focal therapy outside of clinical trials. Our goal was the to review the focal therapy realm for ongoing clinical trials and high impact recently published trials.

Methods: Our comprehensive investigation includes an exhaustive review of ClinicalTrials.gov and PubMed databases, identifying and analyzing clinical trials with diverse modalities of focal therapy. In this review, we focused on critical ongoing and recently concluded clinical trials (2-15-2023) in the focal therapy realm.

Key content and findings: We identified several trials on focal therapy at various stages of progression and various trial design. The trials study all different modalities of focal therapy including high-intensity focused ultrasound (HIFU), cryoablation, irreversible electroporation (IRE), focal laser ablation (FLA), transurethral ultrasound ablation (TULSA)-PRO^®, and Water Vapor ablation. The trials focus both on oncological outcomes and quality of life outcomes. Novel clinical trials study the additive impact of androgen deprivation therapy (ADT) to different focal therapy modalities.

Conclusions: The exploration of focal therapy in prostate cancer holds promise for achieving oncological control while minimizing the impact on patients' quality of life. Continued research and trial results will play a pivotal role in delineating focal therapy's optimal role in the broader prostate cancer treatment spectrum.