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Molecular Diagnosis & Therapy Mar 2022Numerous therapeutic agents specifically targeting the mesenchymal-epithelial transition (MET) oncogene are being developed. (Review)
Review
INTRODUCTION
Numerous therapeutic agents specifically targeting the mesenchymal-epithelial transition (MET) oncogene are being developed.
OBJECTIVE
The aim of the current review was to systematically identify and analyze clinical trials that have evaluated MET inhibitors in various cancer types and to provide an overview of their clinical outcomes.
METHODS
An electronic literature search was carried out in the PubMed and Embase databases to identify published clinical trials related to MET inhibitors. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement was followed for the systematic appraisal of the literature. Data related to clinical outcomes, including progression-free survival, overall survival, objective response rate, and overall tumor response, were extracted.
RESULTS
In total, 49 publications were included. Among these, 51.02% were phase II studies, 14.28% were randomized controlled trials, three were phase III studies, two were prospective observational studies, and the remainder were either phase I or Ib studies. The majority (44.89%) of articles reported the clinical outcomes of MET inhibitors, including small molecules, monoclonal antibodies, and other agents, in patients with non-small-cell lung cancer (NSCLC) harboring MET alterations. MET amplification, overexpression, and MET exon 14 skipping mutations were the major MET alteration types reported across the included studies. Clinical responses/outcomes varied considerably.
CONCLUSION
This systematic literature review provides an overview of the literature available in Embase and PubMed regarding MET-targeted therapies. MET-selective tyrosine kinase inhibitors (TKIs) (capmatinib, tepotinib, and savolitinib) may become a new standard of care in NSCLC, specifically with MET exon 14 skipping mutations. A combination of MET TKIs with epidermal growth factor receptor (EGFR) TKIs (osimertinib + savolitinib, tepotinib + gefitinib) may be a potential solution for MET-driven EGFR TKI resistance. Further, MET alteration (MET amplification/overexpression) may be an actionable target in gastric cancer and papillary renal cell carcinoma.
Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Mutation; Observational Studies as Topic; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met
PubMed: 35266116
DOI: 10.1007/s40291-021-00568-w -
Cell Communication and Signaling : CCS Feb 2020Breast cancer has grown to be the second leading cause of cancer-related deaths in women. Only a few treatment options are available for breast cancer due to the... (Review)
Review
Breast cancer has grown to be the second leading cause of cancer-related deaths in women. Only a few treatment options are available for breast cancer due to the widespread occurrence of chemoresistance, which emphasizes the need to discover and develop new methods to treat this disease. Signal transducer and activator of transcription 3 (STAT3) is an early tumor diagnostic marker and is known to promote breast cancer malignancy. Recent clinical and preclinical data indicate the involvement of overexpressed and constitutively activated STAT3 in the progression, proliferation, metastasis and chemoresistance of breast cancer. Moreover, new pathways comprised of upstream regulators and downstream targets of STAT3 have been discovered. In addition, small molecule inhibitors targeting STAT3 activation have been found to be efficient for therapeutic treatment of breast cancer. This systematic review discusses the advances in the discovery of the STAT3 pathways and drugs targeting STAT3 in breast cancer. Video abstract.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; STAT3 Transcription Factor; Signal Transduction
PubMed: 32111215
DOI: 10.1186/s12964-020-0527-z -
International Journal of Molecular... Aug 2022Background: Glioblastoma (GBM) is a highly aggressive cancer with poor prognosis that needs better treatment modalities. Moreover, there is a lack of reliable biomarkers... (Meta-Analysis)
Meta-Analysis Review
Background: Glioblastoma (GBM) is a highly aggressive cancer with poor prognosis that needs better treatment modalities. Moreover, there is a lack of reliable biomarkers to predict the response and outcome of current or newly designed therapies. While several molecular markers have been proposed as potential biomarkers for GBM, their uptake into clinical settings is slow and impeded by marker heterogeneity. Detailed assessment of prognostic and predictive value for biomarkers in well-defined clinical trial settings, if available, is scattered throughout the literature. Here we conducted a systematic review and meta-analysis to evaluate the prognostic and predictive significance of clinically relevant molecular biomarkers in GBM patients. Material and methods: A comprehensive literature search was conducted to retrieve publications from 3 databases (Pubmed, Cochrane and Embase) from January 2010 to December 2021, using specific terms. The combined hazard ratios (HR) and confidence intervals (95% CI) were used to evaluate the association of biomarkers with overall survival (OS) in GBM patients. Results: Twenty-six out of 1831 screened articles were included in this review. Nineteen articles were included in the meta-analyses, and 7 articles were quantitatively summarised. Fourteen studies with 1231 GBM patients showed a significant association of MGMT methylation with better OS with the pooled HR of 1.66 (95% CI 1.32−2.09, p < 0.0001, random effect). Five studies including 541 GBM patients analysed for the prognostic significance of IDH1 mutation showed significantly better OS in patients with IDH1 mutation with a pooled HR of 2.37 (95% CI 1.81−3.12; p < 0.00001]. Meta-analysis performed on 5 studies including 575 GBM patients presenting with either amplification or high expression of EGFR gene did not reveal any prognostic significance with a pooled HR of 1.31 (95% CI 0.96−1.79; p = 0.08). Conclusions: MGMT promoter methylation and IDH1 mutation are significantly associated with better OS in GBM patients. No significant associations were found between EGFR amplification or overexpression with OS.
Topics: Biomarkers; Biomarkers, Tumor; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; Humans; Tumor Suppressor Proteins
PubMed: 36012105
DOI: 10.3390/ijms23168835 -
Archives of Pathology & Laboratory... Sep 2023To update the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) recommendations for human epidermal growth factor receptor 2 (HER2)...
PURPOSE.—
To update the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. An Update Panel is aware that a new generation of antibody-drug conjugates targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification.
METHODS.—
The Update Panel conducted a systematic literature review to identify signals for updating recommendations.
RESULTS.—
The search identified 173 abstracts. Of 5 potential publications reviewed, none constituted a signal for revising existing recommendations.
RECOMMENDATIONS.—
The 2018 ASCO-CAP recommendations for HER2 testing are affirmed.
DISCUSSION.—
HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 antibody-drug conjugates. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, although it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences. Additional information is available at www.asco.org/breast-cancer-guidelines.
Topics: Humans; Female; Breast Neoplasms; In Situ Hybridization, Fluorescence; Receptor, ErbB-2; In Situ Hybridization; Biomarkers, Tumor
PubMed: 37303228
DOI: 10.5858/arpa.2023-0950-SA -
Scientific Reports Sep 2016CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) plays an important role in tumor progression and a number of studies have suggested that it is an... (Review)
Review
CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) plays an important role in tumor progression and a number of studies have suggested that it is an indicator of tumor prognosis. This current meta-analysis systematically reevaluated the predictive potential of CD147/EMMPRIN in various cancers. We searched PubMed and Embase databases to screen the literature. Fixed-effect and random-effect meta-analytical techniques were used to correlate CD147 expression with outcome measures. A total of 53 studies that included 68 datasets were eligible for inclusion in the final analysis. We found a significant association between CD147/EMMPRIN overexpression and adverse tumor outcomes, such as overall survival, disease-specific survival, progression-free survival, metastasis-free survival or recurrence-free survival, irrespective of the model analysis. In addition, CD147/EMMPRIN overexpression predicted a high risk for chemotherapy drugs resistance. CD147/EMMPRIN is a central player in tumor progression and predicts a poor prognosis, including in patients who have received chemo-radiotherapy. Our results provide the evidence that CD147/EMMPRIN could be a potential therapeutic target for cancers.
Topics: Basigin; Biomarkers, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Neoplasms; Prognosis; Survival Analysis; Up-Regulation
PubMed: 27608940
DOI: 10.1038/srep32804 -
Neuroscience and Biobehavioral Reviews Sep 2016Rodent defense behavior assays have been widely used as preclinical models of anxiety to study possibly therapeutic anxiety-reducing interventions. However, some... (Meta-Analysis)
Meta-Analysis Review
Rodent defense behavior assays have been widely used as preclinical models of anxiety to study possibly therapeutic anxiety-reducing interventions. However, some proposed anxiety-modulating factors - genes, drugs and stressors - have had discordant effects across different studies. To reconcile the effect sizes of purported anxiety factors, we conducted systematic review and meta-analyses of the literature on ten anxiety-linked interventions, as examined in the elevated plus maze, open field and light-dark box assays. Diazepam, 5-HT1A receptor gene knockout and overexpression, SERT gene knockout and overexpression, pain, restraint, social isolation, corticotropin-releasing hormone and Crhr1 were selected for review. Eight interventions had statistically significant effects on rodent anxiety, while Htr1a overexpression and Crh knockout did not. Evidence for publication bias was found in the diazepam, Htt knockout, and social isolation literatures. The Htr1a and Crhr1 results indicate a disconnect between preclinical science and clinical research. Furthermore, the meta-analytic data confirmed that genetic SERT anxiety effects were paradoxical in the context of the clinical use of SERT inhibitors to reduce anxiety.
Topics: Anxiety; Anxiety Disorders; Corticotropin-Releasing Hormone; Humans; Receptors, Corticotropin-Releasing Hormone; Social Isolation
PubMed: 27328783
DOI: 10.1016/j.neubiorev.2016.04.011 -
Indian Journal of Dental Research :... 2017The distinguishing feature of cancer cells is their ability to proliferate indefinitely, which is in contrast to the restricted cell multiplication potential for somatic... (Review)
Review
BACKGROUND
The distinguishing feature of cancer cells is their ability to proliferate indefinitely, which is in contrast to the restricted cell multiplication potential for somatic cells. A better understanding of this contrasting behavior was provided in the early 1990s with the discovery of a relationship between telomeres, telomerase, aging, and cancer. Telomeres (tandem repeat DNA sequence TTAGGG) are protective caps at the ends of human chromosomes. Normal human cells experience telomere shortening with each successive cell division. However, in tumor cells, an overexpression of telomerase confers limitless replicative potential to tumor cells by continuous elongation of telomeres. The objective of this review was to systematically assess the data available on telomerase expression in oral cancer, with special reference to its role in diagnosis, prognosis, and treatment.
MATERIALS AND METHODS
A systematic review of studies that investigated the telomerase expression in oral squamous cell carcinoma (OSCC) was registered with PROSPERO. Subsequent to registration, a predetermined search strategy in accordance with PRISMA guidelines was formulated, and a literature search was conducted using online databases along with hand searching.
RESULTS
Eighty-nine articles from PubMed, 83 from Scopus, 5 from BioMed Central, 43 from Google Scholar, and 2 from hand search were identified. A total of 21 articles were shortlisted that met strict inclusion and exclusion criteria and quality assessment. Each study was evaluated for the markers under study, type of sample used, study design/methodology, and statistical analysis. The studies were then grouped into three subheads depending on their implications in the diagnosis, prognosis, and treatment of OSCC.
CONCLUSION
This review explains the basic biology and the clinical implications of telomerase-based diagnosis and prognosis, the prospects for its use in anticancer therapy, in the context of oral cancer.
Topics: Carcinoma, Squamous Cell; Cell Proliferation; Humans; Mouth Neoplasms; Prognosis; Telomerase; Telomere
PubMed: 29072223
DOI: 10.4103/ijdr.IJDR_690_16 -
JNCI Cancer Spectrum Jan 2024Colorectal cancer (CRC) is the second most common cause of cancer death globally. Recent clinical trials suggest an emerging role for HER2 as a potential clinically... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Colorectal cancer (CRC) is the second most common cause of cancer death globally. Recent clinical trials suggest an emerging role for HER2 as a potential clinically relevant biomarker in CRC. Testing for HER2 in CRC is not standard practice; consequently, the prevalence of HER2 positivity (HER2+) in patients with CRC remains uncertain.
METHODS
A systematic literature review and meta-analysis were conducted to generate estimates of proportions of patients with CRC with HER2 overexpression or HER2 amplification and HER2+ (either overexpression or amplification), overall and in patients with rat sarcoma virus (RAS) wild-type cancer. HER2+ was defined as 1) immunohistochemistry with a score of 3+, 2) immunohistochemistry with a score of 2+ and in situ hybridization+, or 3) next-generation sequencing positive.
RESULTS
Of 224 studies identified with information on HER2 in CRC, 52 studies used a US Food and Drug Administration-approved assay and were selected for further analysis. Estimated HER2+ rate was 4.1% (95% confidence interval [CI] = 3.4% to 5.0%) overall (n = 17 589). HER2+ rates were statistically higher in RAS wild-type (6.1%, 95% CI = 5.4% to 6.9%) vs RAS mutant CRC (1.1%, 95% CI = 0.3% to 4.4%; P < .0001). Despite limited clinical information, we confirmed enrichment of HER2+ CRC in patients with microsatellite stable and left-sided CRC.
CONCLUSION
This meta-analysis provides an estimate of HER2+ CRC and confirms enrichment of HER2 in microsatellite stable, left-sided, RAS wild-type CRC tumors. Our work is important given the recently described clinical efficacy of HER2-targeted therapies in HER2+ CRC and informs strategies for incorporation of HER2 testing into standard of care.
Topics: United States; Humans; Receptor, ErbB-2; Biomarkers, Tumor; Treatment Outcome; Immunohistochemistry; Colorectal Neoplasms
PubMed: 37815820
DOI: 10.1093/jncics/pkad082 -
PloS One 2017Phosphorylated mammalian target of rapamycin (p-mTOR) is a promising prognostic marker in many types of cancer. However, its survival benefit in patients with breast... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Phosphorylated mammalian target of rapamycin (p-mTOR) is a promising prognostic marker in many types of cancer. However, its survival benefit in patients with breast carcinoma remains unknown. The aim of the present study was to assess the relationship between p-mTOR expression and prognosis in breast carcinoma based on a systematic review and meta-analysis.
MATERIALS AND METHODS
Electronic databases (including Pubmed, Embase, ISI web of science, and Cochrane Library) were searched up to November 24, 2015. The outcome measures were hazard ratios (HRs) with 95% confidence interval (CI) for the association between the prognosis of breast carcinoma patients and p-mTOR expression. Primary end points were disease-free survival (DFS), overall survival (OS), and recurrence-free survival (RFS). Statistical analysis was performed with STATA 12.0.
RESULTS
Nine cohort studies including 3051 patients met full eligibility criteria. The pooled HRs (95% CI) for OS, DFS, and RFS were 0.84 (0.27-2.63), 0.71 (0.40-1.23), and 0.48 (0.20-1.18), respectively.
CONCLUSIONS
Our findings suggested that p-mTOR overexpression was not significantly related to prognosis in breast carcinoma regarding OS and disease recurrence. Prospective studies are warranted to examine the association between p-mTOR expression and survival outcomes in breast carcinoma.
Topics: Breast Neoplasms; Female; Humans; Survival Analysis; TOR Serine-Threonine Kinases
PubMed: 28114374
DOI: 10.1371/journal.pone.0170302 -
International Journal of Molecular... Dec 2022Endometriosis is a chronic inflammatory disorder, characterized by the presence of endometrial cells outside the uterine cavity. An increasing number of studies... (Review)
Review
Endometriosis is a chronic inflammatory disorder, characterized by the presence of endometrial cells outside the uterine cavity. An increasing number of studies correlate the immune system with endometriosis, particularly NK receptors (NKR), which have been suggested to play an essential role in the pathogenesis of the disease. This systematic review aims to enlighten the role of NKR in endometriosis. A literature search was performed independently by two reviewers, to identify studies assessing the role of NKR in endometriosis. In total, 18 studies were included. Endometriosis pathogenesis seems to be marked by the overexpression of NK inhibitor receptors (KIRS), namely, CD158a+, KIR2DL1, CD94/NKG2A, PD-1, NKB1, and EB6, and inhibiting ligands such as PD-L1, HLA-E, HLA-G, and HLA-I. Concurrently, there is a decrease in NK-activating receptors and natural cytotoxicity receptors (NCRs), such as NKp46, NKp30, and NKG2D. The immune shift from NK surveillance to NK suppression is also apparent in the greater relative number of ITIM domains compared with ITAM domains in NKRs. In conclusion, NK receptor activity seems to dictate the immunocompetency of women to clear endometriotic cells from the peritoneal cavity. Future research could explore NKRs as therapeutic targets, such as that which is now well established in cancer therapy through immunotherapy.
Topics: Humans; Female; Receptors, Natural Killer Cell; Killer Cells, Natural; Endometriosis; Endometrium
PubMed: 36613776
DOI: 10.3390/ijms24010331