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Frontiers in Pharmacology 2021Poly(ADP-ribose) polymerase (PARP) inhibitors have breakthrough designations for metastatic castration-resistant prostate cancer (mCRPC). We performed a meta-analysis... (Review)
Review
Poly(ADP-ribose) polymerase (PARP) inhibitors have breakthrough designations for metastatic castration-resistant prostate cancer (mCRPC). We performed a meta-analysis of current clinical trials to evaluate the efficacy of PARP inhibitors in mCRPC patients based on their genetic status. On August 2020, PubMed, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for phase II/III clinical studies on PARP inhibitors in mCRPC patients. Data were extracted independently by two investigators and analyzed using Review Manager software version 5.3. Primary endpoints included overall response rate (ORR) and progression-free survival (PFS). Nine clinical trials were identified and analyzed for the clinical benefit of PARP inhibitors in mCRPC patients ( = 1,219). Pooled analyses demonstrated that PARP inhibitors could provide a significant improvement of ORR and PFS in patients with homologous recombination deficiency (HRD) when compared with non-HRD patients. Within the HRD subgroup, mutation patients achieved significantly higher ORR [odds ratio (OR): 9.97, 95% confidence interval (CI): 6.08-16.35] and PFS rates at 12 months (OR: 3.23, 95% CI: 1.71-6.10) when compared with wild-type patients. Furthermore, patients harboring HRD without mutations have a higher objective response after PARP inhibitor treatment compared with non-HRD patients. PARP inhibitor is an effective treatment option for mCRPC patients with mutations in genes related to the HR DNA repair pathway when compared with non-HRD patients. In addition to mutations, other HRD-related gene aberrations may also be used as novel biomarkers to predict the efficacy of PARP inhibitors.
PubMed: 34975480
DOI: 10.3389/fphar.2021.777663 -
International Journal of Molecular... Dec 2021The prevalence of breast cancer in young women (YWBC) has increased alarmingly. Significant efforts are being made to elucidate the biological mechanisms concerning the...
The prevalence of breast cancer in young women (YWBC) has increased alarmingly. Significant efforts are being made to elucidate the biological mechanisms concerning the development, prognosis, and pathological response in early-onset breast cancer (BC) patients. Dysfunctional DNA repair proteins are implied in BC predisposition, progression, and therapy response, underscoring the need for further analyses on DNA repair genes. Public databases of large patient datasets such as METABRIC, TCGA, COSMIC, and cancer cell lines allow the identification of variants in DNA repair genes and possible precision drug candidates. This study aimed at identifying variants and drug candidates that may benefit Latin American (LA) YWBC. We analyzed pathogenic variants in 90 genes involved in DNA repair in public BC datasets from METABRIC, TCGA, COSMIC, CCLE, and COSMIC Cell Lines Project. Results showed that reported DNA repair germline variants in the LA dataset are underrepresented in large databases, in contrast to other populations. Additionally, only six gene repair variants in women under 50 years old from the study population were reported in BC cell lines. Therefore, there is a need for new approaches to study DNA repair variants reported in young women from LA.
Topics: BRCA1 Protein; Breast Neoplasms; DNA Repair; Female; Humans; Latin America; Mutation; Survival Rate; Tumor Suppressor Protein p53
PubMed: 34884835
DOI: 10.3390/ijms222313030 -
Cancers Nov 2021Poly (ADP-ribose) polymerase (PARP) is a DNA damage repair protein, and its inhibitors have shown promising results in clinical trials. The prognostic significance of... (Review)
Review
Poly (ADP-ribose) polymerase (PARP) is a DNA damage repair protein, and its inhibitors have shown promising results in clinical trials. The prognostic significance of PARP is inconsistent in studies of various cancers. In the present study, we conducted a systematic review and meta-analysis to reveal the prognostic and clinicopathological significance of PARP expression in multiple solid cancers. We searched the MEDLINE, EMBASE, and Cochrane databases for relevant research articles published from 2005 to 2021. The pooled hazard ratio (HR) with confidence interval (CI) was calculated to investigate the relationship between PARP expression and survival in multiple solid cancers. In total, 10,667 patients from 31 studies were included. A significant association was found between higher PARP expression and overall survival (OS) (HR = 1.54, 95% CI = 1.34-1.76, < 0.001), disease-free survival (DFS) (HR = 1.15, 95% CI = 1.10-1.21, < 0.001), and progression-free survival (PFS) (HR = 1.05, 95% CI = 1.03-1.08, < 0.001). Subgroup analyses showed that PARP overexpression was significantly related to poor OS in patients with breast cancers (HR = 1.38, 95% CI = 1.28-1.49, < 0.001), ovary cancers (HR = 1.21, 95% CI = 1.10-1.33, = 0.001), lung cancers (HR = 2.11, 95% CI = 1.29-3.45, = 0.003), and liver cancers (HR = 3.29, 95% CI = 1.94-5.58, < 0.001). Regarding ethnicity, Asian people have almost twice their worst survival rate compared to Caucasians. The pooled odds ratio analysis showed a significant relationship between higher PARP expression and larger tumour size, poor tumour differentiation, lymph node metastasis, distant metastasis, higher TNM stage and lymphovascular invasion, and positive immunoreactivity for Ki-67, BRCA1, and BRCA2. In addition, nuclear expression assessed by the QS system using Abcam and Santa Cruz Biotechnology seems to be the most commonly used and reproducible IHC method for assessing PARP expression. This meta-analysis revealed that higher PARP expression was associated with a worse OS, DFS, and PFS in patients with solid cancers. Moreover, inhibition of this pathway through its specific inhibitors may extend the survival of patients with higher PARP expression.
PubMed: 34830749
DOI: 10.3390/cancers13225594 -
Molecular Biotechnology Apr 2022The CRISPR-Cas genome editing system is an intrinsic property of a bacteria-based immune system. This employs a guide RNA to detect and cleave the PAM-associated target... (Review)
Review
The CRISPR-Cas genome editing system is an intrinsic property of a bacteria-based immune system. This employs a guide RNA to detect and cleave the PAM-associated target DNA or RNA in subsequent infections, by the invasion of a similar bacteriophage. The discovery of Cas systems has paved the way to overcome the limitations of existing genome editing tools. In this review, we focus on Cas proteins that are available for gene modifications among which Cas9, Cas12a, and Cas13 have been widely used in the areas of medicine, research, and diagnostics. Since CRISPR has been already proven for its potential research applications, the next milestone for CRISPR will be proving its efficacy and safety. In this connection, we systematically review recent advances in exploring multiple variants of Cas proteins and their modifications for therapeutic applications.
Topics: CRISPR-Cas Systems; DNA; Gene Editing; RNA; RNA, Guide, CRISPR-Cas Systems
PubMed: 34741732
DOI: 10.1007/s12033-021-00422-8 -
Contemporary Oncology (Poznan, Poland) 2021Anaplastic thyroid carcinoma is a rare, rapidly progressing, highly aggressive thyroid malignancy. Responses to immune checkpoint inhibitors in mismatch... (Review)
Review
INTRODUCTION
Anaplastic thyroid carcinoma is a rare, rapidly progressing, highly aggressive thyroid malignancy. Responses to immune checkpoint inhibitors in mismatch repair-deficient/microsatellite instability-high tumours of other locations have shown promising results, and with the extended approval of the PD-1 receptor inhibitor pembrolizumab by the Food and Drug Administration, also anaplastic thyroid cancer (ATC) requires analysis for microsatellite instability (MSI) status.
MATERIAL AND METHODS
Systematic research for relevant literature was conducted in different databases. Prevalence, detection methods, and the potential prognostic/predictive value of MSI in view of the available targeted therapies were of special focus.
RESULTS
Selected citations revealed the prevalence of MSI in 7.4%, with mutations in the MSH2 gene (33%) being the most frequent, followed by MSH6 (25%) and MLH1 (16.7%) occurring in the following combinations: MLH1-MSH2 (8.3%), MSH2-MSH6 (8.3%), and MLH3-MSH5 (8.3%). No mutations in the PMS2 gene were reported. Sixty-six co-mutations in 9 cases were found, with TP53 (88.9%), NF1 (44.4 %), ATM (33.3%), and RB1 (33.3%) being the most frequent. No RAS mutations were noted. Survival ranged between 2.8 and 48 months, and patient age varied between 49 and 84 years. There are insufficient and heterogenous data concerning the predictive or prognostic value of mismatch repair-deficient/microsatellite instability status.
CONCLUSIONS
Tumour molecular profiling is fundamental in ATC for predictive, prognostic, as well as therapeutic reasons, and analysis of MSI status is strongly suggested because a small subgroup show the MSI signature and might profit from recently approved targeted therapies.
PubMed: 34729042
DOI: 10.5114/wo.2021.110052 -
JCO Precision Oncology 2021With the broad use of next-generation sequencing assays, it has become clear that mutations in DNA repair genes are more commonly found than previously reported. In...
PURPOSE
With the broad use of next-generation sequencing assays, it has become clear that mutations in DNA repair genes are more commonly found than previously reported. In advanced prostate cancer patients with 1/2 or mutations, poly (ADP-ribose) polymerase inhibition (PARPi) causes an increased overall survival advantage compared with patients without these mutations. This review explores the advantages and limitations of PARPi treatment and its use beyond 1/2-altered tumors. Furthermore, it discusses the benefits of current biomarkers and what role functional biomarkers and organoids may play in addressing the involvement of homologous recombination repair mutations in tumor development and progression.
METHODS
A systematic review was conducted in MEDLINE, National Library of Medicine, and ClinicalTrials.gov to identify studies published between January 1, 2016, and August 31, 2021. The search strategy incorporated terms for PARPi, BRCA, DNA damage, homologous recombination, organoids, patient-derived organoids, biomarker AND prostate cancer, breast cancer, ovarian cancer.
RESULTS
A total of 261 records remained after duplicate removal, 69 of which were included in the qualitative synthesis.
CONCLUSION
To improve the outcome of targeted therapy and increase sensitivity of tumor detection, patients should be repeatedly screened for DNA repair gene alterations and biomarkers. Future clinical studies should explore the use of PARPi beyond 1/2 mutations and focus on finding new synthetically lethal interactions.
Topics: DNA Damage; Humans; Male; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms; Recombinational DNA Repair
PubMed: 34712892
DOI: 10.1200/PO.21.00152 -
Neuro-oncology Sep 2021The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade... (Meta-Analysis)
Meta-Analysis
MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review.
BACKGROUND
The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use.
METHODS
We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients.
RESULTS
Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP.
CONCLUSIONS
We cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; Glioma; Humans; Methylation; Promoter Regions, Genetic; Temozolomide; Tumor Suppressor Proteins
PubMed: 34467991
DOI: 10.1093/neuonc/noab105 -
Antioxidants (Basel, Switzerland) Jul 2021In patients with varicocele-associated infertility, the effect of antioxidant supplementation on fertility is unknown. We performed a systematic review and meta-analysis... (Review)
Review
In patients with varicocele-associated infertility, the effect of antioxidant supplementation on fertility is unknown. We performed a systematic review and meta-analysis to explore their role in patients with operated or non-operated varicocele. We searched major databases and sources of grey literature until May 2021 (PROSPERO: CRD42021248195). We included 14 studies (980 individuals) in the systematic review. Of the 14 studies, 2 explored the effect of antioxidant supplementation in patients with non-operated varicocele, 1 compared antioxidants versus surgical repair of varicocele, while 11 explored antioxidants after surgical repair of varicocele and were also included in the meta-analysis. Regarding pregnancy rates, no significant differences were demonstrated after treatment with antioxidants versus no treatment at three (OR: 2.28, 95% CI: 0.7-7.48) and six months (OR: 1.88, 95% CI: 0.62-5.72). Accordingly, contradictory findings were reported in sperm concentration, morphology, and motility, as well as DNA fragmentation. Our findings indicate that antioxidant supplementation does not improve pregnancy rates and semen parameters in patients with varicocele-associated infertility, in the absence of previous screening for oxidative stress. Based on the previous notion, most included studies also raised methodological concerns. Therefore, definitive conclusions about the efficacy of antioxidant supplementation in this setting cannot be drawn and further research on the field is mandatory.
PubMed: 34356300
DOI: 10.3390/antiox10071067 -
Ageing Research Reviews Sep 2021Alterations in olfactory functions are proposed to be early biomarkers for neurodegeneration. Many neurodegenerative diseases are age-related, including two of the most... (Review)
Review
Alterations in olfactory functions are proposed to be early biomarkers for neurodegeneration. Many neurodegenerative diseases are age-related, including two of the most common, Parkinson's disease (PD) and Alzheimer's disease (AD). The establishment of biomarkers that promote early risk identification is critical for the implementation of early treatment to postpone or avert pathological development. Olfactory dysfunction (OD) is seen in 90% of early-stage PD patients and 85% of patients with early-stage AD, which makes it an attractive biomarker for early diagnosis of these diseases. Here, we systematically review widely applied smelling tests available for humans as well as olfaction assessments performed in some animal models and the relationships between OD and normal aging, PD, AD, and other conditions. The utility of OD as a biomarker for neurodegenerative disease diagnosis and future research directions are also discussed.
Topics: Aging; Alzheimer Disease; Animals; Humans; Neurodegenerative Diseases; Olfaction Disorders; Parkinson Disease; Smell
PubMed: 34325072
DOI: 10.1016/j.arr.2021.101416 -
Pharmacological Research Sep 2021Glioblastoma multiforme (GBM) is a WHO grade IV glioma and the most common malignant, primary brain tumor with a 5-year survival of 7.2%. Its highly infiltrative nature,...
Glioblastoma multiforme (GBM) is a WHO grade IV glioma and the most common malignant, primary brain tumor with a 5-year survival of 7.2%. Its highly infiltrative nature, genetic heterogeneity, and protection by the blood brain barrier (BBB) have posed great treatment challenges. The standard treatment for GBMs is surgical resection followed by chemoradiotherapy. The robust DNA repair and self-renewing capabilities of glioblastoma cells and glioma initiating cells (GICs), respectively, promote resistance against all current treatment modalities. Thus, durable GBM management will require the invention of innovative treatment strategies. In this review, we will describe biological and molecular targets for GBM therapy, the current status of pharmacologic therapy, prominent mechanisms of resistance, and new treatment approaches. To date, medical imaging is primarily used to determine the location, size and macroscopic morphology of GBM before, during, and after therapy. In the future, molecular and cellular imaging approaches will more dynamically monitor the expression of molecular targets and/or immune responses in the tumor, thereby enabling more immediate adaptation of tumor-tailored, targeted therapies.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Drug Resistance, Neoplasm; Glioblastoma; Humans
PubMed: 34302977
DOI: 10.1016/j.phrs.2021.105780