Exploration of targeted anti-tumor therapy最新文献

Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity.

Cervical cancer remains a significant global health challenge, ranking as the fourth most common cancer among women. Persistent infection with high-risk human papillomavirus (HPV) is the primary etiological factor, leading to immune evasion mechanisms that promote tumor development and progression. Immunotherapy has emerged as a transformative approach in the management of cervical cancer, aiming to restore and enhance the body's immune response against tumor cells. Checkpoint inhibitors targeting programmed death-1 (PD-1) and its ligand (PD-L1) have shown promising results in patients with advanced or recurrent cervical cancer. Pembrolizumab, a PD-1 inhibitor, has been approved for PD-L1-positive cervical cancer, demonstrating durable responses. However, low response rates necessitate exploration of combination strategies. Trials are underway combining checkpoint inhibitors with chemotherapy, radiation, or other immunotherapeutic agents to enhance efficacy. Therapeutic vaccines targeting HPV antigens, such as E6 and E7 oncoproteins, are also a focus of active research. These vaccines aim to elicit robust cytotoxic T-cell responses, offering a potential strategy for early intervention and disease control. Adoptive T-cell therapies, including engineered T-cell receptor (TCR) and chimeric antigen receptor (CAR)-T cells, represent cutting-edge advancements, though challenges with tumor heterogeneity and off-target effects persist. However, challenges such as limited response rates and immune evasion mechanisms remain. The tumor microenvironment (TME) in cervical cancer, characterized by immunosuppressive cells and cytokines, poses a significant barrier to effective immunotherapy. Emerging approaches targeting the TME, such as cytokine modulation, hold promise in overcoming resistance mechanisms. Key gaps include a lack of biomarkers for patient selection, insufficient understanding of TME dynamics, and suboptimal strategies for overcoming antigen heterogeneity and immune resistance. This review addresses these issues by providing a comprehensive analysis of the current landscape of cervical cancer immunotherapy, identifying critical barriers, and highlighting emerging approaches, such as combination therapies, novel immune targets, and strategies to modulate the TME, to guide future research and clinical practice.

Aim: Colorectal cancer is the most prevalent gastrointestinal malignancy with limited therapeutic options in the metastatic setting. The WNT/β-catenin/adenomatous polyposis coli (APC) pathway is commonly deregulated in the disease and presents a rational target for therapeutic exploitation.

Methods: The publicly available genomic data from the colorectal cancer cohort of the Cancer Genome Atlas (TCGA) were used to define groups of colorectal cancers with alterations in APC or other key genes of the WNT/β-catenin/APC pathway and to identify genomic characteristics of interest in each group. In vitro sensitivity data for drugs targeting the pathway were compiled from the Genomics of Drug Sensitivity in Cancer (GDSC) project.

Results: Three-fourths of colorectal cancers possessed APC alterations and about one in four of these cases possessed also concomitant alterations in other genes of the WNT/β-catenin/APC pathway, including RNF43, CTNNB1, and TCF7L2. Colorectal cancers with alterations in one or more of the three genes of the WNT/β-catenin pathway, RNF43, CTNNB1, and TCF7L2, in the absence of APC alterations, were frequently microsatellite instability (MSI) high and had high tumor mutation burden (TMB). Cancers with these same alterations in the three genes with or without APC alterations presented a high frequency of mutations in receptor tyrosine kinases, PI3K/AKT pathway genes, and DNA damage response genes. Cell lines without mutations in WNT/β-catenin/APC pathway components displayed numerically greater sensitivity to inhibitors of the pathway in vitro.

Conclusions: Groups of colorectal cancers differing in WNT/β-catenin/APC pathway alterations present diverse genomic landscapes that could have therapeutic implications for the rational development of inhibitors of the pathway.

Glioblastoma, an aggressive and lethal brain tumor, presents enormous clinical challenges, including molecular heterogeneity, high recurrence rates, resistance to conventional therapies, and limited therapeutic penetration across the blood-brain barrier. The glioblastoma microenvironment, characterized by a dynamic interplay of cellular and non-cellular components, is a key driver of tumor growth and therapeutic resistance. Neuroinflammatory cytokines, particularly interleukins and tumor necrosis factor-alpha, play pivotal roles in this microenvironment, contributing to tumor progression and immune evasion. This review highlights oncolytic virotherapy as a promising therapeutic avenue, focusing on its potential to modulate neuroinflammatory responses, induce localized immune reactions, and deliver immunomodulatory factors directly to the tumor site. While encouraging outcomes have been observed, challenges such as overcoming the blood-brain barrier, managing host antiviral immunity, and mitigating potential risks to normal neuronal cells remain critical barriers to clinical translation. By analyzing the intricate interactions of oncolytic viruses with the glioblastoma microenvironment and synthesizing findings from preclinical and clinical trials, this review provides actionable insights into developing personalized and effective therapeutic strategies for this aggressive tumor based on oncolytic virotherapy alone or when using it combined with conventional therapies, immunotherapy, natural killer-cell therapy, chimeric antigen receptor-T cell therapy, and dendritic cell therapy.

Background: Breast cancer is a leading cause of mortality in women. Hormone therapy plays a crucial role in treatment of hormone receptor-positive metastatic breast cancer. Elacestrant is a selective estrogen receptor degrader (SERD) that has shown promise in early-phase clinical trials. This post-hoc analysis systematically evaluates elacestrant's effectiveness in hormone receptor-positive metastatic breast cancer patients, providing insights into its efficacy, safety, and potential advantages over existing treatments.

Methods: We adhered to the PRISMA Statement 2020 guidelines and systematically searched the databases PubMed/MEDLINE, ClinicalTrials.gov, Web of Science, and Embase. We conducted the post-hoc analysis using R software (V 4.3.3), applying the inverse variance method and the DerSimonian-Laird estimator to pool effect estimates with a random-effects model. We assessed heterogeneity using the Cochran's Q test and the I ² statistic.

Results: Our post-hoc analysis encompassed 3 clinical trials and a total of 835 participants. The mean age of all 835 participants across the three trials was 59.5 years (95% CI: 58.7-60.3). The pooled progression-free survival (PFS)-was estimated at 4.38 (95% CI: -7.58-16.35, P = 0.47), and the pooled objective response rate (ORR) was 7% (95% CI: 2-18%, P = 0.04), with significant heterogeneity observed among the studies.

Discussion: Elacestrant shows promise for improving outcomes in hormone receptor-positive metastatic breast cancer, but further research is needed to confirm its effectiveness. Future studies should include larger sample sizes, comprehensive phase II and III trials, and investigation of elacestrant in combination with other drugs or in preoperative settings.

Laryngeal cancer, a subtype of head and neck cancer, poses significant challenges due to its profound impact on essential functions such as speech and swallowing and poor survival rates in advanced stages. Traditional treatments-surgery, radiotherapy, and chemotherapy-are often associated with high morbidity and substantial recurrence rates, emphasizing the urgent need for novel therapeutic approaches. Immune checkpoint inhibitors (ICIs) have revolutionized oncology by countering tumor-induced immune evasion, restoring immune surveillance, and activating T-cell responses against cancer. This review examines the role of ICIs in laryngeal cancer management, with a focus on pembrolizumab and nivolumab (anti-PD-1 agents), which are clinically established, as well as investigational therapies such as dostarlimab (anti-PD-1), atezolizumab (anti-PD-L1), and ipilimumab (anti-CTLA-4). Pembrolizumab, in combination with platinum-based chemotherapy and 5-fluorouracil, is approved as a first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), based on evidence from the Keynote-048 trial. This pivotal trial demonstrated significant overall survival (OS) benefits over the cetuximab-based standard regimen. Similarly, nivolumab showed improved OS in the CheckMate-141 trial, supporting its approval as a second-line therapy for patients with platinum-refractory disease. ICIs have shown durable survival benefits and a more manageable toxicity profile compared to traditional chemotherapy. Immune-related adverse events are generally mild and controllable; however, in some cases, they can become severe and even life-threatening. Furthermore, ICIs are being investigated in combination with radiotherapy, as well as in neoadjuvant and adjuvant settings, where preliminary findings suggest these approaches may enhance efficacy, preserve organ function, and overcome resistance to conventional treatments. The integration of ICIs into multimodal treatment strategies holds promise for transforming the therapeutic landscape of advanced laryngeal cancer. This review synthesizes current evidence, highlights ongoing research, and explores strategies to enhance survival and quality of life for patients facing this challenging malignancy.

Background: Preclinical animal studies have demonstrated that radiation treatment (RT) can induce effects beyond the anatomical site of irradiation. Non-targeted effects of RT (NTER) have been sporadically reported in clinical settings. However, with the advent of high-dose stereotactic radiation techniques (SRT) and immunotherapy (IT), renewed attention has been given to NTER. This systematic review aims to summarize current knowledge about NTER across various malignancies, with a focus on cases involving SRT.

Methods: A systematic database search was performed, and records were screened following PRISMA guidelines. Only full-text original articles written in English and reporting clinical studies involving NTER after SRT were included. The results are categorized by cancer type, with separate general and critical analyses.

Results: Sixty-three studies were reviewed, including 32 case reports/case series, 18 retrospective studies, and 13 prospective studies, predominantly published after 2018. NTER was most frequently observed in melanoma and lung cancer and commonly reported as the abscopal effect (AE), albeit with varying criteria. In most cases, IT with suboptimal response was ongoing at the time of SRT, and the median time to NTER onset was 3 months. Overall, NTER was documented in 297 patients: 34 from single cases and 263 from a pool of 1,212 evaluable patients (22%) across other studies. Prospective trials reported an NTER rate of 36%, rising to 56% in lung cancer.

Discussion: In prospective clinical studies, the phenomenon of NTER following SRT has been observed in a significant proportion of patients. Nevertheless, the literature is limited, with small patient cohorts. Interest in NTER has grown, particularly in the context of IT. Standardization of definitions and reporting, along with the conduct of more clinical trials, is essential to better understand how NTER can be induced by SRT.

Multikinase inhibitors (MKIs) and highly selective tyrosine kinase inhibitors (HS-TKIs) positively impact the progression-free survival (PFS) of locally advanced and metastatic thyroid cancer cases. Moreover, disease-specific survival (DSS) and overall survival (OS) improvements were observed in some instances, suggesting a general benefit in disease control. In advanced and metastatic thyroid cancers, other conventional treatments are often ineffective when surgery cannot be performed due to the extension of the disease and/or the invasion of vital neck structures (such as the larynx, trachea, esophagus, recurrent laryngeal nerve, and carotid artery). In these cases, systemic treatments with MKIs and HS-TKIs have recently been evaluated for their potential to block tumor growth and reduce tumor size to make surgery possible or improve the control of metastatic disease. The study aimed to evaluate the performance of these systemic drugs in the neoadjuvant treatment of thyroid cancer patients, focusing on their efficacy according to the different histology.

Background: Telomere length is a potential prognostic biomarker in breast cancer, but its clinical utility remains uncertain due to inconsistent findings across the literature. This systematic review and meta-analysis aims to evaluate the association between telomere length and breast cancer survival outcomes, including overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and recurrence-free survival (RFS).

Methods: A systematic search of ten sources, including databases and publishers (JSTOR, Nature, ProQuest, PubMed, Sage Journals, ScienceDirect, Science, Scopus, Springer, and Wiley) was conducted to identify studies published up to December 31, 2023. Studies reporting associations between telomere length and survival outcomes in breast cancer patients were included. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CI) were extracted or calculated. Quality assessment was performed using the Newcastle-Ottawa Scale, and publication bias was evaluated using funnel plots, Egger's, and Begg's tests.

Results: Nine studies involving 3,145 breast cancer patients were included. Shorter telomere length was significantly associated with increased recurrence risk (DFS/RFS) (pooled HR: 1.97; 95% CI: 1.04-3.74, P = 0.039), indicating a nearly twofold increase in risk. Trends toward worse OS (pooled HR: 1.60; 95% CI: 0.90-2.86, P = 0.110) and DSS (pooled HR: 1.09; 95% CI: 0.80-1.49, P = 0.565) were observed, but did not reach statistical significance. Additionally, shorter telomere length was significantly associated with premenopausal status (pooled OR: 1.34; 95% CI: 1.06-1.70, P = 0.01).

Discussion: Shorter telomere length is associated with an increased risk of recurrence in breast cancer, highlighting its potential as a prognostic biomarker. However, further research is needed to standardize telomere length measurement methodologies and validate these findings across diverse populations and breast cancer subtypes.

Bladder cancer is currently the most common malignant tumor of the urinary system. The traditional treatment methods for bladder cancer are mainly surgery, chemotherapy, radiotherapy, and targeted therapy; however, these treatment methods do not improve the clinical prognosis of patients with advanced or metastatic bladder cancer. Consequently, there is an urgent need to develop new treatment methods to improve the survival rate and quality-of-life of patients with bladder cancer. Over recent years, the rapid development of tumor immunotherapy has become a significant alternative to traditional treatment, and provides new hope to patients. This review aims to introduce neoantigens and their possible role in the treatment of bladder cancer, and to explore the current limitations of neoantigens for the treatment of bladder cancer.