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Medicina (Kaunas, Lithuania) Dec 2023: Several recent randomized controlled trials (RCTs) have reported on the survival benefits of poly (ADP-ribose) polymerase inhibitors (PARPi) compared to... (Meta-Analysis)
Meta-Analysis Review
: Several recent randomized controlled trials (RCTs) have reported on the survival benefits of poly (ADP-ribose) polymerase inhibitors (PARPi) compared to standard-of-care (SOC) treatment (enzalutamide, abiraterone, or docetaxel) in patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is a limited integrated analysis of high-quality evidence comparing the efficacy and safety of PARPi and SOC treatments in this context. : This study aims to comprehensively analyze the survival benefits and adverse events associated with PARPi and SOC treatments through a head-to-head meta-analysis in mCRPC. : A systematic review search was conducted in PubMed, Embase, Clinical trials, and the Central Cochrane Registry in July 2023. RCTs were assessed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The systematic review was prospectively registered on PROSPERO (CRD42023441034). : A total of 8 studies, encompassing 2341 cases in the PARPi treatment arm and 1810 cases in the controlled arm, were included in the qualitative synthesis. The hazard ratio (HR) for radiographic progression-free survival (rPFS) and overall survival (OS) were 0.74 (95% CI, 0.61-0.90) and 0.89 (95% CI, 0.80-0.99), respectively, in the intention-to-treatment patients. For subgroup analysis, HRs for rPFS and OS in the BRCA-mutated subgroup were 0.39 (95% CI, 0.28-0.55) and 0.62 (95% CI, 0.38-0.99), while in the HRR-mutated subgroup, HR for rPFS was 0.57 (95% CI, 0.48-0.69) and for OS was 0.77 (95% CI, 0.64-0.93). The odds ratio (OR) for all grades of adverse events (AEs) and AEs with severity of at least grade 3 were 3.86 (95% CI, 2.53-5.90) and 2.30 (95% CI, 1.63-3.26), respectively. : PARP inhibitors demonstrate greater effectiveness than SOC treatments in HRR/BRCA-positive patients with mCRPC. Further research is required to explore ways to reduce adverse event rates and investigate the efficacy of HRR/BRCA-negative patients.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Ribose; Disease-Free Survival; Randomized Controlled Trials as Topic
PubMed: 38138301
DOI: 10.3390/medicina59122198 -
Current Oncology (Toronto, Ont.) Dec 2023Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for... (Review)
Review
Preclinical and clinical studies have suggested potential synergies of combining poly (ADP-ribose) polymerase (PARP) inhibitors and novel hormonal therapies (NHT) for patients with metastatic castration-resistant prostate cancer (mCRPC). We systematically searched PubMed, ClinicalTrials.gov and ASCO-GU annual meeting abstracts up to March 2023 to identify potential phase III trials reporting the use of combining PARP inhibitors with NHT in the first-line setting for mCRPC. A total of four phase III trials met the criteria for subsequent review. Emerging data suggested that the radiographic progression-free survival (rPFS) was significantly longer in the PARP inhibitor combined with NHT group versus the placebo plus NHT group for the first-line setting of biomarker-unselected mCRPC patients, especially for patients with homologous recombination repair (HRR) mutation (HRR m), and with the greatest benefit for BRCA1/2 mutation (BRCA1/2 m) populations. Final overall survival (OS) data of the PROpel trial indicated a significant improvement in median OS for mCRPC patients with HRR m and BRCA1/2 m receiving olaparib + abiraterone. Prior taxane-based chemotherapy might not influence the efficacy of the combination. Compared with the current standard-of-care therapies, combining NHT with PARP inhibitors could achieve a significant survival benefit in the first-line setting for mCRPC patients with HRR and BRCA1/2 mutations.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; BRCA1 Protein; Ribose; BRCA2 Protein; Antineoplastic Agents
PubMed: 38132385
DOI: 10.3390/curroncol30120751 -
Journal of Cachexia, Sarcopenia and... Jun 2024Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for...
BACKGROUND
Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy.
METHODS
We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-C]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level.
RESULTS
The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: -36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-C]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e-8).
CONCLUSIONS
Understanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.
Topics: Glucose; Muscle, Skeletal; Animals; Mice; Humans; Hypertrophy; Muscle Fibers, Skeletal; Insulin-Like Growth Factor I; Metabolomics
PubMed: 38742477
DOI: 10.1002/jcsm.13468 -
Asian Journal of Surgery Dec 2023
Meta-Analysis
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Ribose; Ovarian Neoplasms; Mutation
PubMed: 37541880
DOI: 10.1016/j.asjsur.2023.07.118