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BMC Women's Health Jan 2024Both mitophagy and long non-coding RNAs (lncRNAs) play crucial roles in ovarian cancer (OC). We sought to explore the characteristics of mitophagy-related gene (MRG) and...
BACKGROUND
Both mitophagy and long non-coding RNAs (lncRNAs) play crucial roles in ovarian cancer (OC). We sought to explore the characteristics of mitophagy-related gene (MRG) and mitophagy-related lncRNAs (MRL) to facilitate treatment and prognosis of OC.
METHODS
The processed data were extracted from public databases (TCGA, GTEx, GEO and GeneCards). The highly synergistic lncRNA modules and MRLs were identified using weighted gene co-expression network analysis. Using LASSO Cox regression analysis, the MRL-model was first established based on TCGA and then validated with four external GEO datasets. The independent prognostic value of the MRL-model was evaluated by Multivariate Cox regression analysis. Characteristics of functional pathways, somatic mutations, immunity features, and anti-tumor therapy related to the MRL-model were evaluated using abundant algorithms, such as GSEA, ssGSEA, GSVA, maftools, CIBERSORT, xCELL, MCPcounter, ESTIMATE, TIDE, pRRophetic and so on.
RESULTS
We found 52 differentially expressed MRGs and 22 prognostic MRGs in OC. Enrichment analysis revealed that MRGs were involved in mitophagy. Nine prognostic MRLs were identified and eight optimal MRLs combinations were screened to establish the MRL-model. The MRL-model stratified patients into high- and low-risk groups and remained a prognostic factor (P < 0.05) with independent value (P < 0.05) in TCGA and GEO. We observed that OC patients in the high-risk group also had the unfavorable survival in consideration of clinicopathological parameters. The Nomogram was plotted to make the prediction results more intuitive and readable. The two risk groups were enriched in discrepant functional pathways (such as Wnt signaling pathway) and immunity features. Besides, patients in the low-risk group may be more sensitive to immunotherapy (P = 0.01). Several chemotherapeutic drugs (Paclitaxel, Veliparib, Rucaparib, Axitinib, Linsitinib, Saracatinib, Motesanib, Ponatinib, Imatinib and so on) were found with variant sensitivity between the two risk groups. The established ceRNA network indicated the underlying mechanisms of MRLs.
CONCLUSIONS
Our study revealed the roles of MRLs and MRL-model in expression, prognosis, chemotherapy, immunotherapy, and molecular mechanism of OC. Our findings were able to stratify OC patients with high risk, unfavorable prognosis and variant treatment sensitivity, thus improving clinical outcomes for OC patients.
Topics: Female; Humans; RNA, Long Noncoding; Mitophagy; Ovarian Neoplasms; Paclitaxel; Axitinib; Prognosis
PubMed: 38218807
DOI: 10.1186/s12905-023-02864-5 -
Expert Review of Anticancer Therapy 2024Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) treatment for ovarian cancer (OC) are ever-changing. This study aimed to compare the efficacy and... (Comparative Study)
Comparative Study Meta-Analysis Review
Comparison of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance therapy for newly-diagnosed and platinum-sensitive recurrent ovarian cancer with mutational status: a systematic review and network meta-analysis.
BACKGROUND
Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) treatment for ovarian cancer (OC) are ever-changing. This study aimed to compare the efficacy and overall safety of available PARPi as maintenance therapy for BRCA mutation status in patients with newly diagnosed and platinum-sensitive recurrent (PSR) OC patients.
RESEARCH DESIGN AND METHODS
Relevant RCTs were systematically retrieved from PubMed and Embase until 31 May 2022. Progression-free survival (PFS) and overall survival (OS) based on mutation status and adverse events (AEs) regardless of mutation were efficacy and safety endpoints.
RESULTS
In newly diagnosed BRCAm-OC patients, olaparib (HR: 0.33; 95% confidence interval [CI]: 0.25, 0.43) and other PARPis [niraparib (HR: 0.40; 95% CI: 0.29, 0.55), rucaparib (HR: 0.40; 95% CI: 0.21, 0.76) and veliparib (HR: 0.44; 95% CI: 0.28, 0.69)] had a statistically significant effect on PFS versus placebo. In BRCAm-PSROC patients, Olaparib exhibited significant benefit (HR: 0.69; 95% CI: 0.54, 0.88) for OS compared to other PARPis. In BRCAwt-PSR OC patients, Olaparib showed a favorable OS benefit than other PARPis (HR: 0.84; 95% CI: 0.57,1.22). Overall, safety profile of all PARPis was acceptable.
CONCLUSION
All PARPis showed significant benefit, with olaparib showing greater benefit in newly diagnosed and PSR OC women.
REGISTRATION
CRD42021288932.
Topics: Female; Humans; Adenosine Diphosphate; Carcinoma, Ovarian Epithelial; Neoplasm Recurrence, Local; Network Meta-Analysis; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Ribose
PubMed: 38174379
DOI: 10.1080/14737140.2023.2298832 -
Cell Cycle (Georgetown, Tex.) Nov 2023Homologous repair deficiency (HRD) impedes double-strand break repair, which is a common driver of carcinogenesis. Positive HRD status can be used as theranostic markers...
Homologous repair deficiency (HRD) impedes double-strand break repair, which is a common driver of carcinogenesis. Positive HRD status can be used as theranostic markers of response to platinum- and PARP inhibitor-based chemotherapies. Here, we aimed to fully investigate the therapeutic and prognostic potential of HRD in pancreatic adenocarcinoma (PAAD) and identify effective biomarkers related to HRD using comprehensive bioinformatics analysis. The HRD score was defined as the unweighted sum of the LOH, TAI, and LST scores, and it was obtained based on the previous literature. To characterize PAAD immune infiltration subtypes, the "ConsensusClusterPlus" package in R was used to conduct unsupervised clustering. A WGCNA was conducted to elucidate the gene coexpression modules and hub genes in the HRD-related gene module of PAAD. The functional enrichment study was performed using Metascape. LASSO analysis was performed using the "glmnet" package in R, while the random forest algorithm was realized using the "randomForest" package in R. The prognostic variables were evaluated using univariate Cox analysis. The prognostic risk model was built using the LASSO approach. ROC curve and KM survival analyses were performed to assess the prognostic potential of the risk model. The half-maximal inhibitory concentration (IC50) of the PARP inhibitors was estimated using the "pRRophetic" package in R and the Genomics of Drug Sensitivity in Cancer database. The "rms" package in R was used to create the nomogram. A high HRD score indicated a poor prognosis and an advanced clinical process in PAAD patients. PAAD tumors with high HRD levels revealed significant T helper lymphocyte depletion, upregulated levels of cancer stem cells, and increased sensitivity to rucaparib, Olaparib, and veliparib. Using WGCNA, 11 coexpression modules were obtained. The red module and 122 hub genes were identified as the most correlated with HRD in PAAD. Functional enrichment analysis revealed that the 122 hub genes were mainly concentrated in cell cycle pathways. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were screened via LASSO analysis and a random forest algorithm, and they were validated using independent validation sets. No direct association between HRD and , , or has not been reported in the literature so far. Thus, these findings indicated that , , and have potential as diagnostic and prognostic biomarkers for PAAD. We constructed a novel HRD-related prognostic model that provides new insights into PAAD prognosis and immunotherapy. Based on bioinformatics analysis, we comprehensively explored the therapeutic and prognostic potential of HRD in PAAD. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were identified through the combination of WGCNA, LASSO analysis and a random forest algorithm. A novel HRD-related risk model that can predict clinical prognosis and immunotherapeutic response in PAAD patients was constructed.
Topics: Humans; Adenocarcinoma; Pancreatic Neoplasms; Genes, cdc; Machine Learning; Biomarkers
PubMed: 38124367
DOI: 10.1080/15384101.2023.2293594 -
The Journal of Gene Medicine Jan 2024Patients with triple-negative breast cancer (TNBC) often have a poor prognostic outcome. Current treatment strategies cannot benefit all TNBC patients. Previous findings...
BACKGROUND
Patients with triple-negative breast cancer (TNBC) often have a poor prognostic outcome. Current treatment strategies cannot benefit all TNBC patients. Previous findings suggested pyroptosis as a novel target for suppressing cancer development, although the relationship between TNBC and pyroptosis-related genes (PRGs) was still unclear.
METHODS
Gene expression data and clinical follow-up of TNBC patients were collected from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO). PRGs were screened using weighted gene co-expression network analysis. Cox regression analysis and the least absolute shrinkage and selection operator (i.e. LASSO) technique were applied to construct a pyroptosis-related prognostic risk score (PPRS) model, which was further combined with the clinicopathological characteristics of TNBC patients to develop a survival decision tree and a nomogram. The model was used to calculate the PPRS, and then the overall survival, immune infiltration, immunotherapy response and drug sensitivity of TNBC patients were analyzed based on the PPRS.
RESULTS
The PPRS model was closely related to clinicopathological features and can independently and accurately predict the prognosis of TNBC. According to normalized PPRS, patients in different cohorts were divided into two groups. Compared with the high-PPRS group, the low-PPRS group had significantly higher ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) score, immune score and stromal score, and it also had overexpressed immune checkpoints and significantly reduced Tumor Immune Dysfunction and Exclusion (TIDE) score, as well as higher sensitivity to paclitaxel, veliparib, olaparib and talazoparib. A decision tree and nomogram based on PPRS and clinical characteristics can improve the prognosis stratification and survival prediction for TNBC patients.
CONCLUSIONS
A PPRS model was developed to predict TNBC patients' immune characteristics and response to immunotherapy, chemotherapy and targeted therapy, as well as their survival outcomes.
Topics: Humans; Triple Negative Breast Neoplasms; Pyroptosis; Immunotherapy; Risk Factors; Gene Expression Profiling
PubMed: 38041540
DOI: 10.1002/jgm.3645 -
Journal of Neuro-oncology Dec 2023A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP]...
PURPOSE
A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP] enzyme inhibitor, when administered with temozolomide (TMZ) alone and then with temozolomide and radiation (RT) in patients with newly diagnosed glioblastoma.
METHODS
Given the potential for myelosuppression when a PARP inhibitor is combined with chemotherapy, the first 6 patients accrued were given Veliparib 10 mg bid and TMZ 75 mg/m2/d daily for six weeks. If this was well tolerated, the same doses of Veliparib and TMZ would be tested along with standard radiation with plans to dose escalate the Veliparib in subsequent patient cohorts. Once a maximal tolerated dose was determined, a 78 patient phase II study was planned. Peripheral blood pharmacokinetics were assessed.
RESULTS
Twenty-four patients were enrolled. In the first 6 patients who received 6 weeks of TMZ with Veliparib only one dose limiting toxicity (DLT) occurred. The next 12 patients received 6 weeks of RT + TMZ + veliparib and 4/12 (33%) had dose limiting hematologic toxicities. As a result, Veliparib was reduced by 50% to 10 mg BID every other week, but again 3/3 patients had dose limiting hematologic toxicities. The trial was then terminated. The mean clearance (± SD) CL/F of Veliparib for the initial dose (27.0 ± 9.0 L/h, n = 16) and at steady-state for 10 mg BID (23.5 ± 10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56% (± 33%).
CONCLUSIONS
Although Veliparib 10 mg BID administered with TMZ 75 mg/m2 for six weeks was well tolerated, when this regimen was combined with standard partial brain irradiation it was severely myelosuppressive even when the dose was reduced by 50%. This study again highlights the potential of localized cranial radiotherapy to significantly increase hematologic toxicity of marginally myelosuppressive systemic therapies.
Topics: Humans; Temozolomide; Glioblastoma; Antineoplastic Agents; Benzimidazoles; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms
PubMed: 38015376
DOI: 10.1007/s11060-023-04514-0 -
Computers in Biology and Medicine Jan 2024PARP-1 (Poly (ADP-ribose) polymerase 1) is a nuclear enzyme and plays a key role in many cellular functions, such as DNA repair, modulation of chromatin structure, and...
PARP-1 (Poly (ADP-ribose) polymerase 1) is a nuclear enzyme and plays a key role in many cellular functions, such as DNA repair, modulation of chromatin structure, and recombination. Developing the PARP-1 inhibitors has emerged as an effective therapeutic strategy for a growing list of cancers. The catalytic structural domain (CAT) of PARP-1 upon binding the inhibitor allosterically regulates the conformational changes of helix domain (HD), affecting its identification with the damaged DNA. The typical type I (EB47) and III (veliparib) inhibitors were able to lengthening or shortening the retention time of this enzyme on DNA damage and thus regulating the cytotoxicity. Nonetheless, the basis underlying allosteric inhibition is unclear, which limits the development of novel PARP-1 inhibitors. Here, to investigate the distinct allosteric changes of EB47 and veliparib against PARP-1 CAT, each complex was simulated via classical and Gaussian accelerated molecular dynamics (cMD and GaMD). To study the reverse allosteric basis and mutation effects, the complexes PARP-1 with UKTT15 and PARP-1 D766/770A mutant with EB47 were also simulated. Importantly, the markov state models were built to identify the transition pathways of crucial substates of allosteric communication and the induction basis of PARP-1 reverse allostery. The conformational change differences of PARP-1 CAT regulated by allosteric inhibitors were concerned with to their interaction at the active site. Energy calculations suggested the energy advantage of EB47 in inhibiting the wild-type PARP-1, compared with D766/770A PARP-1. Secondary structure results showed the change of two key loops (αB-αD and αE-αF) in different systems. This work reported the basis of PARP-1 allostery from both thermodynamic and kinetic views, providing the guidance for the discovery and design of more innovative PARP-1 allosteric inhibitors.
Topics: DNA Damage; DNA Repair; Molecular Dynamics Simulation; Mutation; Poly(ADP-ribose) Polymerase Inhibitors; Humans
PubMed: 38000246
DOI: 10.1016/j.compbiomed.2023.107682 -
Journal of Chemotherapy (Florence,... Nov 2023We conducted a meta-analysis to evaluate the efficacy and safety of veliparib in the treatment of advanced/metastatic breast cancer. Databases were searched for relevant... (Review)
Review
We conducted a meta-analysis to evaluate the efficacy and safety of veliparib in the treatment of advanced/metastatic breast cancer. Databases were searched for relevant studies till June 2023. Six RCTs involving 1912 patients were included. The pooled analysis provided evidence that veliparib-containing regimens could significantly improve the PFS (HR: 0.71; 95% CI: 0.61-0.83; < 0.0001), OS (HR: 0.87; 95% CI: 0.76-0.99; = 0.03), and ORR (RR: 1.52; 95% CI:1.06-2.18; = 0.02) than those of controls for treating advanced/metastatic breast cancer. Breast cancer patients with -mutation tended to have a better PFS than the -wildtype group, and patients with TNBC tended to associated with a longer PFS than the non-TNBC group. Veliparib could significantly increase the risk of anemia, leukopenia, neutropenia, diarrhea, stomatitis, fatigue, and peripheral neuropathy. Anemia and neutropenia should be well concerned. The veliparib-containing regimen was efficacious in treating advanced/metastatic breast cancer with a controllable safety factor.
PubMed: 37975589
DOI: 10.1080/1120009X.2023.2281760 -
PeerJ 2023Lung cancer, originating from bronchial mucosa or lung glands, poses significant health risks due to its rising incidence and mortality. This study aimed to assess the... (Review)
Review Meta-Analysis
OBJECTIVE
Lung cancer, originating from bronchial mucosa or lung glands, poses significant health risks due to its rising incidence and mortality. This study aimed to assess the efficacy and safety of Veliparib combined with chemotherapy versus pharmacotherapy alone for lung cancer treatment, guiding clinical approaches for this severe disease.
METHODS
Comprehensive searches in PubMed, EMBASE, Cochrane, and Web of Science were conducted to identify randomized controlled trials (RCTs) comparing Veliparib combined with standard chemotherapy to chemotherapy alone in lung cancer treatment, up until December 28, 2022. Two reviewers meticulously selected literature based on inclusion and exclusion criteria. The Cochrane tool was used to assess the bias risk of the included studies, and meta-analysis was performed using Stata 15.0.
RESULTS
Five RCTs (1,010 participants) were included. The analysis results showed that only Veliparib combinedwith chemotherapy prolonged the progression-free survival (PFS) in small cell lung cancer (SCLC) patients [HR = 0.72, 95% CI = (0.57, 0.90)]. No significant differences were observed in overall survival (OS) and objective response rate (ORR). Veliparib and combined chemotherapy caused some side effects in patients with lung cancer, including leukopenia [RR = 2.12, 95% CI = (1.27, 3.55)], neutropenia [RR = 1.51, 95% CI = (1.01, 2.26)], anemia [RR = 1.71, 95% CI = (1.07, 3.07)], and thrombocytopenia [RR = 3.33, 95% CI = (1.19, 9.30)]. For non-small cell lung cancer (NSCLC) patients, there were no statistically significant differences in PFS, OS, or ORR between the experimental and control groups [HR = 0.97, 95% CI = (0.75, 1.27)].
CONCLUSION
The strategy of combining Veliparib with chemotherapy may, to some extent, prolong the PFS in lung cancer patients. However, this benefit is not observed in OS or ORR. Additionally, there are evident adverse reactions. Due to a limited number of the included studies, additional extensive multicenter RCTs are required to validate these results. PROSPERO registration number: CRD42023411510.
Topics: Humans; Antineoplastic Agents; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Benzimidazoles; Multicenter Studies as Topic
PubMed: 37965288
DOI: 10.7717/peerj.16402 -
Research Square Oct 2023A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP]...
PURPOSE
A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP] enzyme inhibitor, when administered with temozolomide (TMZ) alone and then with temozolomide and radiation (RT) in patients with newly diagnosed glioblastoma.
METHODS
Given the potential for myelosuppression when a PARP inhibitor is combined with chemotherapy, the first 6 patients accrued were given Veliparib 10 mg bid and TMZ 75 mg/m2/d daily for six weeks. If this was well tolerated, the same doses of Veliparib and TMZ would be tested along with standard radiation with plans to dose escalate the Veliparib in subsequent patient cohorts. Once a maximal tolerated dose was determined, a 78 patient phase II study was planned. Peripheral blood pharmacokinetics were assessed.
RESULTS
Twenty-four patients were enrolled. In the first 6 patients who received 6 weeks of TMZ with Veliparib only one dose limiting toxicity (DLT) occurred. The next 12 patients received 6 weeks of RT + TMZ + veliparib and 4/12 (33%) had dose limiting hematologic toxicities. As a result, Veliparib was reduced by 50% to 10 mg BID every other week, but again 3/3 patients had dose limiting hematologic toxicities. The trial was then terminated. The mean clearance (± SD) CL/F of Veliparib for the initial dose (27.0 ± 9.0 L/h, n = 16) and at steady-state for 10 mg BID (23.5 ± 10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56% (± 33%).
CONCLUSIONS
Although Veliparib 10 mg BID administered with TMZ 75 mg/m2 for six weeks was well tolerated, when this regimen was combined with standard partial brain irradiation it was severely myelosuppressive even when the dose was reduced by 50%. This study again highlights the potential of localized cranial radiotherapy to significantly increase hematologic toxicity of marginally myelosuppressive systemic therapies.
PubMed: 37961385
DOI: 10.21203/rs.3.rs-3466927/v1 -
Seminars in Oncology 2024PARP inhibitors have emerged as a promising class of anticancer agents approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. These inhibitors... (Review)
Review
PARP inhibitors have emerged as a promising class of anticancer agents approved for the treatment of ovarian, breast, prostate, and pancreatic cancer. These inhibitors target PARP enzymes involved in DNA repair pathways and exhibit remarkable efficacy in cancers with genetic deficiencies in the homologous recombination pathway responsible for mending DNA double-strand breaks. While all PARP inhibitors demonstrate potent and selective inhibition of PARP1 and PARP2, the key enzymes involved in DNA repair, each agent within the class possesses unique pharmacological profiles distinguishing them from one another. This review aims to comprehensively examine the properties of the entire PARP inhibitor class while emphasizing individual pharmacologic and pharmacokinetic distinctions that inform clinical recommendations. Currently, four agents, namely olaparib, rucaparib, niraparib, and talazoparib, have obtained approval in the United States and Europe. Olaparib, the first approved PARP inhibitor, has been extensively studied and is indicated for a wider range of cancer types. Niraparib and talazoparib, the more recent additions to the PARP inhibitor class, possess the longest half-lives and are formulated for convenient once-daily dosing, alleviating the pill burden for patients when compared to older agents. Moreover, talazoparib undergoes minimal hepatic metabolism, reducing the potential for drug-drug interactions. Notably, niraparib is the sole PARP inhibitor recommended for dose reduction in hepatically impaired populations, whereas talazoparib and olaparib should be dose reduced in renally impaired populations. The mechanisms underlying these dose adjustment recommendations are further explored in this review. Additionally, this review briefly covers veliparib, a PARP inhibitor under development, and two recently approved PARP inhibitors in China, fuzuloparib and pamiparib. Although significant progress has been made in understanding PARP inhibitors, there are several unanswered questions that remain, necessitating further research across a broader spectrum of cancer types within this evolving class of anticancer agents.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Pharmacogenetics; Antineoplastic Agents; Neoplasms; Ovarian Neoplasms
PubMed: 37880048
DOI: 10.1053/j.seminoncol.2023.09.005