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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 -
Oral Oncology Mar 2021We report the results of this phase I study to evaluate the maximum tolerated dose (MTD) and safety of veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor,...
A phase I trial adding poly(ADP-ribose) polymerase inhibitor veliparib to induction carboplatin-paclitaxel in patients with head and neck squamous cell carcinoma: Alliance A091101.
OBJECTIVES
We report the results of this phase I study to evaluate the maximum tolerated dose (MTD) and safety of veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin and paclitaxel induction chemotherapy (IC) for locoregionally advanced head and neck squamous cell carcinoma (HNSCC).
MATERIALS AND METHODS
In a 3 + 3 cohort design, patients with stage IVA-B human papillomavirus-negative HNSCC received 2 cycles of carboplatin (AUC 6, day 1), paclitaxel (100 mg/m, days 1, 8, 15) and veliparib (days 1-7) every 21 days followed by standard curative-intent chemoradiotherapy. Primary endpoint: MTD and recommended phase II dose (RP2D) as determined by the first IC cycle.
RESULTS
Twenty patients enrolled. Two withdrew before treatment; 18 patients were analyzed. Median age was 63 years. Primary disease sites included hypopharynx (n = 5), larynx (n = 5), oral cavity (n = 4), oropharynx (n = 3), and nasal cavity (n = 1). Through all of IC, the most common grade 3 + adverse events (AEs) were neutropenia (33%), thrombocytopenia (33%), anemia (11%), and white blood cell decrease (11%). One patient experienced a hematologic DLT at 350 mg BID. The RP2D for veliparib combined with carboplatin/paclitaxel is 350 mg BID. With 40.9 month median follow-up across dose levels for all patients, the 24-month overall and progression free survival was 77.8% (95% CI 60.8-99.6%) and 66.7% (95% CI 48.1-92.4%), respectively. Medians have not been reached.
CONCLUSION
Addition of veliparib to carboplatin and paclitaxel IC was well tolerated in patients with advanced HNSCC. Hematologic toxicities were the most common AEs.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Female; Humans; Male; Middle Aged; Paclitaxel; Poly(ADP-ribose) Polymerase Inhibitors; Squamous Cell Carcinoma of Head and Neck; Young Adult
PubMed: 33513474
DOI: 10.1016/j.oraloncology.2020.105171 -
Cancer Chemotherapy and Pharmacology Aug 2019Time is a critical factor in drug action. The duration of inhibition of the target or residence time of the drug molecule on the target often guides drug scheduling.
PURPOSE
Time is a critical factor in drug action. The duration of inhibition of the target or residence time of the drug molecule on the target often guides drug scheduling.
METHODS
The effects of time on the concentration-dependent cytotoxicity of approved and investigational agents [300 compounds] were examined in the NCI60 cell line panel in 2D at 2, 3, 7 and in 3D 11 days.
RESULTS
There was a moderate positive linear relationship between data from the 2-day NCI60 screen and the 3-, 7- and 11-day and a strong positive linear relationship between 3-, 7- and 11-day luminescence screen ICs by Pearson correlation analysis. Cell growth inhibition by agents selective for a specific cell cycle phase plateaued when susceptible cells were growth inhibited or killed. As time increased the depth of cell growth inhibition increased without change in the IC. DNA interactive agents had decreasing ICs with increasing exposure time. Epigenetic agents required longer exposure times; several were only cytotoxic after 11 days' exposure. For HDAC inhibitors, time had little or no effect on concentration response. There were potency differences amongst the three BET bromodomain inhibitors tested, and an exposure duration effect. The PARP inhibitors, rucaparib, niraparib, and veliparib reached ICs < 10 μM in some cell lines after 11 days.
CONCLUSIONS
The results suggest that variations in compound exposure time may reflect either mechanism of action or compound chemical half-life. The activity of slow-acting compounds may optimally be assessed in spheroid models that can be monitored over prolonged incubation times.
Topics: Antineoplastic Agents; Cell Line, Tumor; Humans
PubMed: 31102023
DOI: 10.1007/s00280-019-03863-w -
Therapeutic Advances in Medical Oncology 2021To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative,...
Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: subgroup analyses by germline / mutations and hormone receptor status from the phase-3 BROCADE3 trial.
PURPOSE
To evaluate efficacy and safety of veliparib combined with carboplatin/paclitaxel in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, germline (g)-associated breast cancer defined by hormone receptor (HR) and g/ mutation status.
PATIENTS AND METHODS
In this phase-3, double-blind, placebo-controlled trial, patients ( = 509) with advanced HER2-negative breast cancer and g mutations were randomized 2:1 to receive veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Patients who discontinued chemotherapy prior to disease progression continued receiving blinded veliparib/placebo monotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Subgroup analyses of PFS stratified by HR and g mutation status were prespecified.
RESULTS
In the intention-to-treat population, there were similar proportions of patients with g g mutations (51% 49%) and HR+ disease triple-negative breast cancer (TNBC) (52% 48%). Median PFS was longer in the veliparib arm compared with the placebo arm for all subgroups (HR+: 13.0 12.5 months, hazard ratio (95% confidence interval (CI)): 0.69 (0.52, 0.93), = 0.013; TNBC: 16.6 14.1 months, hazard ratio (95% CI): 0.72 (0.52, 1.00), = 0.052; g: 14.2 12.6 months, hazard ratio (95% CI): 0.75 (0.55, 1.03), = 0.073; g: 14.6 12.6 months, hazard ratio (95% CI): 0.69 (0.50, 0.95); = 0.021). Benefit was durable, with improved PFS rates at 2 years (HR+, 27.5% 15.3%; TNBC, 40.4% 25.0%) and 3 years (HR+, 17.5% 8.6%; TNBC, 35.3% 13.0%) in all subgroups. g status () did not substantially affect the carboplatin/paclitaxel ± veliparib toxicity profile.
CONCLUSION
Veliparib plus carboplatin/paclitaxel resulted in durable benefit in subgroups defined by HR status or by g g mutation. Overall, addition of veliparib to carboplatin/paclitaxel was tolerable, and there were no clinically meaningful differences in adverse events between the g g and HR+ TNBC subgroups.
TRIAL REGISTRATION
NCT02163694, https://clinicaltrials.gov/ct2/show/NCT02163694.
PubMed: 34917174
DOI: 10.1177/17588359211059601 -
Open Medicine (Warsaw, Poland) 2023More clinical evidence is needed regarding the relative priority of treatments for brain metastases (BMs) from EGFR/ALK-negative/unselected non-small cell lung cancer...
More clinical evidence is needed regarding the relative priority of treatments for brain metastases (BMs) from EGFR/ALK-negative/unselected non-small cell lung cancer (NSCLC). PubMed, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov databases were searched. Overall survival (OS), central nervous system progression-free survival (CNS-PFS), and objective response rate (ORR) were selected for Bayesian network meta-analyses. We included 25 eligible randomized control trials (RCTs) involving 3,054 patients, investigating nine kinds of treatments for newly diagnosed BMs and seven kinds of treatments for previously treated BMs. For newly diagnosed BMs, adding chemotherapy, EGFR-TKIs, and other innovative systemic agents (temozolomide, nitroglycerin, endostar, enzastaurin, and veliparib) to radiotherapy did not significantly prolong OS than radiotherapy alone; whereas radiotherapy + nitroglycerin showed significantly better CNS-PFS and ORR. Surgery could significantly prolong OS (hazard ratios [HR]: 0.52, 95% credible intervals: 0.41-0.67) and CNS-PFS (HR: 0.32, 95% confidence interval: 0.18-0.59) compared with radiotherapy alone. For previously treated BMs, pembrolizumab + chemotherapy, nivolumab + ipilimumab, and cemiplimab significantly prolonged OS than chemotherapy alone. Pembrolizumab + chemotherapy also showed better CNS-PFS and ORR than chemotherapy. In summary, immune checkpoint inhibitor (ICI)-based therapies, especially ICI-combined therapies, showed promising efficacies for previously treated BMs from EGFR/ALK-negative/unselected NSCLC. The value of surgery should also be emphasized. The result should be further confirmed by RCTs.
PubMed: 36820064
DOI: 10.1515/med-2022-0574 -
Neuro-oncology Jun 2020A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly...
BACKGROUND
A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: (i) estimate the recommended phase II dose (RP2D) of veliparib with concurrent radiation; (ii) evaluate the pharmacokinetic parameters of veliparib during radiation; (iii) evaluate feasibility of intrapatient TMZ dose escalation; (iv) describe toxicities of protocol therapy; and (v) estimate the overall survival distribution compared with historical series.
METHODS
Veliparib was given Monday through Friday b.i.d. during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 b.i.d. and TMZ 135 mg/m2 daily for 5 days every 28 days. Intrapatient dose escalation of TMZ was investigated for patients experiencing minimal toxicity.
RESULTS
Sixty-six patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 b.i.d. with radiation. Dose-limiting toxicities during radiation with veliparib therapy included: grade 2 intratumoral hemorrhage (n = 1), grade 3 maculopapular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). Intrapatient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared with PBTC historical controls, and accrual was stopped for futility. The 1- and 2-year overall survival rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively.
CONCLUSION
Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG.
TRIAL REGISTRATION
NCT01514201.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Brain Neoplasms; Brain Stem Neoplasms; Child; Glioma; Humans; Temozolomide
PubMed: 32009149
DOI: 10.1093/neuonc/noaa016 -
American Journal of Translational... 2022MiR-199a-3p was previously predicted to target tumor suppressor gene , which has been linked to cancer onset and therapeutic response. In this study, the effects of...
MiR-199a-3p was previously predicted to target tumor suppressor gene , which has been linked to cancer onset and therapeutic response. In this study, the effects of miR-199a-3p-mediated dysfunction on triple-negative breast cancer (TNBC) progression and chemosensitivity were assessed. The association between miR-199a-3p and expression was examined in TNBC tumors and verified with luciferase reporter and protein assays. Tumorigenic functions of miR-199a-3p in TNBC cells were investigated by cell proliferation, clonogenic and migration assays. The sensitivities to chemotherapeutic drugs were tested with cisplatin and PARP inhibitor (veliparib) treatments. Mouse xenograft model was used to examine the effects of miR-199a-3p on tumor growth and drug response . MiR-199a-3p was shown to directly target in TNBC cells, resulting its downregulation and reduced luciferase reporter activity mediated by 3'-UTR. Ectopic miR-199a-3p in TNBC cells exerted inhibitory effects on cell proliferation, migration and xenograft tumor growth. Moreover, miR-199a-3p was shown to reverse cisplatin-resistance and sensitize TNBC cells to veliparib, which might be due to repressed DNA repair ability and induced cell apoptosis. Our results demonstrated the tumor suppressive effects of miR-199a-3p on TNBC and induction on chemotherapeutic sensitivities, which were correlated with gene dysfunction. These findings may provide insights into the potential prognostic and therapeutic values of miR-199a-3p in patients with TNBC.
PubMed: 35422914
DOI: No ID Found -
Blood Advances Nov 2021Poly(ADP-ribose) polymerase 1 (PARP1) is a key mediator of various forms of DNA damage repair and plays an important role in the progression of several cancer types. The... (Review)
Review
Poly(ADP-ribose) polymerase 1 (PARP1) is a key mediator of various forms of DNA damage repair and plays an important role in the progression of several cancer types. The enzyme is activated by binding to DNA single-strand and double-strand breaks. Its contribution to chromatin remodeling makes PARP1 crucial for gene expression regulation. Inhibition of its activity with small molecules leads to the synthetic lethal effect by impeding DNA repair in the treatment of cancer cells. At first, PARP1 inhibitors (PARPis) were developed to target breast cancer mutated cancer cells. Currently, PARPis are being studied to be used in a broader variety of patients either as single agents or in combination with chemotherapy, antiangiogenic agents, ionizing radiation, and immune checkpoint inhibitors. Ongoing clinical trials on olaparib, rucaparib, niraparib, veliparib, and the recent talazoparib show the advantage of these agents in overcoming PARPi resistance and underline their efficacy in targeted treatment of several hematologic malignancies. In this review, focusing on the crucial role of PARP1 in physiological and pathological effects in myelodysplastic syndrome and acute myeloid leukemia, we give an outline of the enzyme's mechanisms of action and its role in the pathophysiology and prognosis of myelodysplastic syndrome/acute myeloid leukemia and we analyze the available data on the use of PARPis, highlighting their promising advances in clinical application.
Topics: Breast Neoplasms; DNA Repair; Female; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 34529761
DOI: 10.1182/bloodadvances.2021004638 -
Frontiers in Molecular Biosciences 2021Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new...
Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan-Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.
PubMed: 33996894
DOI: 10.3389/fmolb.2021.633344 -
International Journal of Molecular... Feb 2021The high incidence of skin cancers in the Caucasian population is primarily due to the accumulation of DNA damage in epidermal cells induced by chronic ultraviolet B...
The high incidence of skin cancers in the Caucasian population is primarily due to the accumulation of DNA damage in epidermal cells induced by chronic ultraviolet B (UVB) exposure. UVB-induced DNA photolesions, including cyclobutane-pyrimidine dimers (CPDs), promote mutations in skin cancer driver genes. In humans, CPDs are repaired by nucleotide excision repair (NER). Several commonly used and investigational medications negatively influence NER in experimental systems. Despite these molecules' ability to decrease NER activity in vitro, the role of these drugs in enhancing skin cancer risk is unclear. In this study, we investigated four molecules (veliparib, resveratrol, spironolactone, and arsenic trioxide) with well-known NER-inhibitory potential in vitro, using UVB-irradiated CHO epithelial and HaCaT immortalized keratinocyte cell lines. Relative CPD levels, hypoxanthine phosphoribosyltransferase gene mutation frequency, cell viability, cell cycle progression, and protein expression were assessed. All four molecules significantly elevated CPD levels in the genome 24 h after UVB irradiation. However, veliparib, spironolactone, and arsenic trioxide reduced the mutagenic potential of UVB, while resveratrol did not alter UVB-induced mutation formation. UVB-induced apoptosis was enhanced by spironolactone and arsenic-trioxide treatment, while veliparib caused significantly prolonged cell cycle arrest and increased autophagy. Spironolactone also enhanced the phosphorylation level of mammalian target of rapamycin (mTOR), while arsenic trioxide modified UVB-driven mitochondrial fission. Resveratrol induced only mild changes in the cellular UVB response. Our results show that chemically inhibited NER does not result in increased mutagenic effects. Furthermore, the UVB-induced mutagenic potential can be paradoxically mitigated by NER-inhibitor molecules. We identified molecular changes in the cellular UVB response after NER-inhibitor treatment, which may compensate for the mitigated DNA repair. Our findings show that metabolic cellular response pathways are essential to consider in evaluating the skin cancer risk-modifying effects of pharmacological compounds.
Topics: Animals; Arsenic Trioxide; Autophagy; Benzimidazoles; CHO Cells; Cell Cycle Checkpoints; Cell Line, Transformed; Cell Survival; Cricetulus; DNA Damage; DNA Repair; HaCaT Cells; Humans; Hypoxanthine Phosphoribosyltransferase; Melanoma; Mutation Rate; Pyrimidine Dimers; Resveratrol; Skin; Skin Neoplasms; Spironolactone; Ultraviolet Rays
PubMed: 33562002
DOI: 10.3390/ijms22041638