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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 -
Journal of Clinical Oncology : Official... Aug 2023To update ASCO-College of American Pathologists (CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. The Panel is aware...
PURPOSE
To update ASCO-College of American Pathologists (CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. The Panel is aware that a new generation of antibody-drug conjugates (ADCs) targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification.
METHODS
An Update Panel conducted a systematic literature review to identify signals for updating recommendations.
RESULTS
The search identified 173 abstracts. Of five 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 ADCs. 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, while 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; Pathologists; Receptor, ErbB-2; Biomarkers, Tumor
PubMed: 37284804
DOI: 10.1200/JCO.22.02864 -
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 -
Molecular Cancer Therapeutics Apr 2022The Nectin cell adhesion protein 4 (Nectin-4) is overexpressed in multiple human malignancies. Such aberrant expression is correlated with cancer progression and poor...
The Nectin cell adhesion protein 4 (Nectin-4) is overexpressed in multiple human malignancies. Such aberrant expression is correlated with cancer progression and poor prognostic. Nectin-4 has emerged as a potential biomarker and promising targeted therapy. This review aimed to gather the current state of the literature about Nectin-4 relevance in preclinical tumor models and to summarize its clinical relevance regarding cancer. A systematic assessment of literature articles was performed by searching in PUBMED (MEDLINE) from the database inception to May 2021, following PRISMA guidelines. Preclinical models unanimously demonstrated membrane and cytoplasmic location of the Nectin-4. Furthermore, Nectin-4 was overexpressed whatever the location of the solid tumors. Interestingly, a heterogeneity of Nectin-4 expression has been highlighted in bladder urothelial carcinoma. High serum Nectin-4 level was correlated with treatment efficiency and disease progression. Finally, generated anti-drug-conjugated targeting Nectin-4 induced cell death in multiple tumor cell lines. Nectin-4 emerges as a promising target for anticancer drugs development because of its central role in tumorigenesis, and lymphangiogenesis. Enfortumab vedotin targeting Nectin-4 demonstrated encouraging results and should be extended to other types of solid tumors.
Topics: Antineoplastic Agents; Carcinoma, Transitional Cell; Cell Adhesion Molecules; Cell Line, Tumor; Humans; Immunoconjugates; Urinary Bladder Neoplasms
PubMed: 35131876
DOI: 10.1158/1535-7163.MCT-21-0846 -
Journal of Clinical Neuroscience :... Nov 2022Vasospasm is a common complication following subarachnoid hemorrhage (SAH), causing increased ischemia and tissue injury, and is implicated as a major risk factor for... (Review)
Review
INTRODUCTION
Vasospasm is a common complication following subarachnoid hemorrhage (SAH), causing increased ischemia and tissue injury, and is implicated as a major risk factor for poor outcomes. The success of current treatments for vasospasm is limited, with limited efficacy and unclear clinical benefits. Exosomes, vesicles that carry small molecules such as miRNA, have been theorized as a potential vasospasm treatment. In this study, we aim to survey the current literature discussing the role of exosomes in the setting of SAH.
METHODS
Following PRISMA guidelines, we performed a scoping review evaluating the role of exosomes in the treatment of SAH. The search was conducted using PubMed and Scopus, and all original research papers studying exosomal profiles of SAH research subjects or SAH therapy were eligible for inclusion.
RESULTS
After screening and full text review, seven papers were selected for final inclusion. Of these, two studies analyzed the expression profile of endogenous exosomes after SAH. Four papers identified and characterized miRNA-based exosomal therapies to attenuate early brain injury (EBI) after SAH. One paper discussed the role of protein overexpression in exosome delivery of miRNA for EBI after SAH. Interestingly, all identified papers studying exosomal therapy demonstrated anti-apoptotic or anti-inflammatory effects of miRNA exosomes acting via the BDNF/TrkB/CREB or HDAC3/NF-κB pathways.
CONCLUSION
Identified studies demonstrate potential neuroprotective benefits of miRNA-based exosomal treatment of EBI and SAH. Findings warrant further research investigating the anti-inflammatory and anti-apoptotic role of exosomal miRNA delivery in SAH models, specifically targeting the common pathway identified by the authors.
Topics: Anti-Inflammatory Agents; Brain Injuries; Brain-Derived Neurotrophic Factor; Exosomes; Humans; MicroRNAs; NF-kappa B; Subarachnoid Hemorrhage
PubMed: 36084567
DOI: 10.1016/j.jocn.2022.08.025 -
BMJ Supportive & Palliative Care Dec 2022P-cadherin can act both as a tumour suppressor and an oncogene. The clinical prognostic value of P-cadherin overexpression in breast cancer (BC) remains unclear. We... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
P-cadherin can act both as a tumour suppressor and an oncogene. The clinical prognostic value of P-cadherin overexpression in breast cancer (BC) remains unclear. We conducted a study-level meta-analysis to determine whether P-cadherin expression can help predict prognosis in BC.
METHODS
A systematic literature search was performed to review eligible studies and clarify the relationship between P-cadherin overexpression and overall survival (OS), disease-free survival (DFS), pathological features, molecular subtypes and molecular phenotypes in BC.
RESULTS
Thirty-one studies including 12 332 patients were included. P-cadherin overexpression was correlated with significantly worse OS (HR=1.77, p<0.00001) and DFS (HR=1.96, p0.00001) than P-cadherin-negative. P-cadherin overexpression could lead to high histological grade (OR=3.33, p<0.00001) and lymph node metastasis (OR=1.62, p<0.00001). Moreover, P-cadherin overexpression was associated with low odds of the luminal A subtype and high odds of the human epidermal growth factor receptor-2 (HER2)-positive and triple-negative subtypes. P-cadherin expression led to low expression of oestrogen and progesterone receptor (OR=0.37 and OR=0.36, respectively, both p<0.00001) and high expression of HER2 (OR=2.31, p<0.00001), Ki-67 (OR=2.79, p<0.00001), epidermal growth factor receptor (OR=5.85, p<0.00001) and cytokeratin 5/6 (OR=6.79, p<0.00001).
CONCLUSIONS
P-cadherin was found to be associated with invasiveness and metastasis. P-cadherin expression can probably be a useful biomarker for predicting poor survival and may act as an independent prognostic predictor.
Topics: Humans; Female; Breast Neoplasms; Prognosis; Cadherins; Disease-Free Survival; Lymphatic Metastasis
PubMed: 32943470
DOI: 10.1136/bmjspcare-2020-002204 -
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 -
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