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ACS Medicinal Chemistry Letters May 2023Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments in BRCA1/2 mutated breast and...
Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments in BRCA1/2 mutated breast and ovarian cancers. Mounting evidence also supports their application as neuroprotective agents since PARP overactivation compromises the mitochondrial homeostasis by consumption of NAD reserves, leading to an increase in reactive oxygen and nitrogen species and a spike in intracellular Ca levels. Herein, we present the synthesis and preliminary evaluation of new mitochondria-targeting PARP inhibitor prodrugs of (±)-veliparib, with the goal to advance potential neuroprotective properties without impairing the repair of damaged DNA in the nucleus.
PubMed: 37197461
DOI: 10.1021/acsmedchemlett.3c00065 -
Journal of Ovarian Research Apr 2023Ovarian cancer (OV), the most fatal gynecological malignance worldwide, has high recurrence rates and poor prognosis. Recently, emerging evidence supports that...
Ovarian cancer (OV), the most fatal gynecological malignance worldwide, has high recurrence rates and poor prognosis. Recently, emerging evidence supports that autophagy, a highly regulated multi-step self-digestive process, plays an essential role in OV progression. Accordingly, we filtered 52 potential autophagy-related genes (ATGs) among the 6197 differentially expressed genes (DEGs) identified in TCGA-OV samples (n = 372) and normal controls (n = 180). Based on the LASSO-Cox analysis, we distinguished a 2-gene prognostic signature, namely FOXO1 and CASP8, with promising prognostic value (p-value < 0.001). Together with corresponding clinical features, we constructed a nomogram model for 1-year, 2-year, and 3-year survival, which was validated in both in training (TCGA-OV, p-value < 0.001) and validation (ICGC-OV, p-value = 0.030) cohorts. Interestingly, we evaluated the immune infiltration landscape through the CIBERSORT algorithm, which indicated the upregulation of 5 immune cells, including CD8 + T cells, Tregs, and Macrophages M2, and high expression of critical immune checkpoints (CTLA4, HAVCR2, PDCD1LG2, and TIGIT) in high-risk group. Stepwise, high-risk group exhibited better sensitivity towards chemotherapies of Bleomycin, Sorafenib, Veliparib, and Vinblastine, though less sensitive to immunotherapy. Especially, based on the IHC of tissue microarrays among 125 patients in our institution, we demonstrated that aberrant upregulation of FOXO1 in OV was related to metastasis and poor prognosis. Moreover, FOXO1 could significantly promote tumor invasiveness, migration, and proliferation in OV cell lines, which was assessed through the Transwell, wound-healing, and CCK-8 assay, respectively. Briefly, the autophagy-related signature was a reliable tool to evaluate immune responses and predict prognosis in the realm of OV precision medicine.
Topics: Humans; Female; Prognosis; Autophagy; Ovarian Neoplasms; Nomograms; Algorithms; Tumor Microenvironment
PubMed: 37120633
DOI: 10.1186/s13048-023-01167-5 -
DNA Repair Jun 2023Laser micro-irradiation across the nucleus rapidly generates localized chromatin-associated DNA lesions permitting analysis of repair protein recruitment in living...
Laser micro-irradiation across the nucleus rapidly generates localized chromatin-associated DNA lesions permitting analysis of repair protein recruitment in living cells. Recruitment of three fluorescently-tagged base excision repair factors [DNA polymerase β (pol β), XRCC1 and PARP1], known to interact with one another, was compared in gene-deleted mouse embryonic fibroblasts and in those expressing the endogenous factor. A low energy micro-irradiation (LEMI) forming direct single-strand breaks and a moderate energy (MEMI) protocol that additionally creates oxidized bases were compared. Quantitative characterization of repair factor recruitment and sensitivity to clinical PARP inhibitors (PARPi) was dependent on the micro-irradiation protocol. PARP1 recruitment was biphasic and generally occurred prior to pol β and XRCC1. After LEMI, but not after MEMI, pol β and XRCC1 recruitment was abolished by the PARPi veliparib. Consistent with this, pol β and XRCC1 recruitment following LEMI was considerably slower in PARP1-deficient cells. Surprisingly, the recruitment half-times and amplitudes for pol β were less affected by PARPi than were XRCC1 after MEMI suggesting there is a XRCC1-independent component for pol β recruitment. After LEMI, but not MEMI, pol β dissociation was more rapid than that of XRCC1. Unexpectedly, PARP1 dissociation was slowed in the absence of XRCC1 as well with a PARPi after LEMI but not MEMI, suggesting that XRCC1 facilitates PARP1 dissociation from specific DNA lesions. XRCC1-deficient cells showed pronounced hypersensitivity to the PARPi talazoparib correlating with its known cytotoxic PARP1 trapping activity. In contrast to DNA methylating agents, PARPi only minimally sensitized pol β and XRCC1-deficient cells to oxidative DNA damage suggesting differential binding of PARP1 to alternate repair intermediates. In summary, pol β, XRCC1, and PARP1 display recruitment kinetics that exhibit correlated and unique properties that depend on the DNA lesion and PARP activity revealing that there are multiple avenues utilized in the repair of chromatin-associated DNA.
Topics: Animals; Mice; Fibroblasts; DNA Repair; DNA Damage; X-ray Repair Cross Complementing Protein 1; Poly (ADP-Ribose) Polymerase-1; DNA; Poly(ADP-ribose) Polymerases; Chromatin; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 37028218
DOI: 10.1016/j.dnarep.2023.103486 -
Hematology/oncology and Stem Cell... Apr 2023The PARP inhibitors (PARPis) olaparib and talazoparib are currently approved for the treatment of deleterious germline BRCA1/2-mutated (gBRCA+) metastatic breast cancer... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The PARP inhibitors (PARPis) olaparib and talazoparib are currently approved for the treatment of deleterious germline BRCA1/2-mutated (gBRCA+) metastatic breast cancer (MBC). These approvals were based on improvements in progression-free survival (PFS) observed in two randomized controlled trials (RCTs). Other PARPis, such as veliparib and niraparib, have also been studied. We conducted this meta-analysis of RCTs to assess the PFS and overall survival (OS) benefits of PARPis in gBRCA + MBC.
METHODS
We performed a systematic search for RCTs using the Cochrane Library, PubMed, Embase, and Web of Science databases up to March 2021. Only phase II and III RCTs evaluating PFS and OS for PARPis alone or in combination with chemotherapy (CT) and comparing the findings with standard CT were included in this meta-analysis. Pooled analysis of the hazard ratio (HR) was performed with RevMan v5.4 using a random effects method.
RESULTS
Five RCTs with a total of 1563 BRCA-mutated MBC patients were included in this meta-analysis. Temozolomide was used in the treatment arm in the BROCADE trial. Since temozolomide has limited effects on breast cancer, this arm was excluded from our meta-analysis. A statistically significant increase in PFS was observed in the PARPi group compared to the standard CT group (HR, 0.64; 95% CI, 0.56-0.74; P < 0.00001). However, the differences in OS did not reach statistical significance (HR, 0.89; 95% CI, 0.77-1.02; P = 0.09). Moreover, differences were not observed in the adverse event profile between the two groups (odds ratio, 1.18; 95% CI, 0.84-1.64; P = 0.33).
CONCLUSION
The results of our meta-analysis confirm the previously reported PFS benefit of PARPis over standard CT. PARPis lead to superior PFS in gBRCA + MBC when used alone or in combination with standard CT. The OS benefit is similar between PARPis and standard CT. Ongoing trials are evaluating the benefits of PARPis in early stage gBRCA + BC.
Topics: Female; Humans; BRCA1 Protein; Breast Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Temozolomide; BRCA2 Protein
PubMed: 37023220
DOI: 10.56875/2589-0646.1033 -
The Oncologist May 2023Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors,...
BACKGROUND
Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors, but such combinations have proven too toxic in clinical trials. Liposomal irinotecan (nal-IRI) achieved similar intratumoral exposure with better antitumor activity than the conventional TOP1 inhibitor irinotecan in preclinical models. Tumor targeted delivery of TOP1 inhibitor using nal-IRI and an intermittent schedule of administration of PARP inhibitor may provide a tolerable combination.
METHODS
A phase I study was performed to evaluate the safety and tolerability of escalating doses of nal-IRI and the PARP inhibitor veliparib in patients with solid tumors resistant to standard treatments. Nal-IRI was administered on days 1 and 15 and veliparib on days 5-12 and 19-25 in 28-day cycles.
RESULTS
Eighteen patients were enrolled across 3 dose levels. Five patients encountered dose-limiting toxicities, including grade 3 diarrhea lasting more than 72 h in 3 patients and 1 patient each with grade 4 diarrhea and grade 3 hyponatremia. The most common grade 3 or 4 toxicities included diarrhea (50% of patients), nausea (16.6%), anorexia, and vomiting (11.1% each) (Table 1). There was no difference in frequencies of adverse events based on UGT1A1*28 status or prior opioid use (Table 1).
CONCLUSION
The clinical trial was terminated due to high frequency of unacceptable gastrointestinal toxicities, which precluded dose escalation of veliparib in combination with nal-IRI (ClinicalTrials.gov Identifier: NCT02631733).
Topics: Humans; Irinotecan; Poly(ADP-ribose) Polymerase Inhibitors; Neoplasms; Antineoplastic Agents; Topoisomerase I Inhibitors; Poly(ADP-ribose) Polymerases; Diarrhea; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37010988
DOI: 10.1093/oncolo/oyad023 -
Oncology Letters Apr 2023Poly (ADP ribose) polymerase (PARP) inhibitors are novel targeted anticancer agents that have been widely used in patients with cancer, particularly in patients with... (Review)
Review
Poly (ADP ribose) polymerase (PARP) inhibitors are novel targeted anticancer agents that have been widely used in patients with cancer, particularly in patients with breast-related cancer antigen 1/2 mutations. PARP inhibitors are administered orally and have been associated with improved efficacy and toxicity profiles when compared to conventional chemotherapy agents; this improvement is convenient and results in good compliance among patients with cancer. However, as PARP inhibitors are administered long-term and frequently concomitantly with other therapeutic agents, the risk of drug-drug interactions (DDIs) is increasing. Transporters are widely expressed in numerous types of tissue, where they have crucial roles in the membrane transport of several drugs. An alteration in the activity and expression of transporters may change the drug pharmacokinetics (PKs) and cause DDIs. As the five PARP inhibitors (olaparib, niraparib, rucaparib, talazoparib and veliparib) are transporter substrates, inhibitors or inducers, the potential transporter-mediated DDIs with the use of PARP inhibitors should be taken into consideration when co-administered with other agents. The present review focused on recent findings on transporter-mediated DDIs with PARP inhibitors to provide specific recommendations for reducing the occurrence of undesired DDIs.
PubMed: 36936025
DOI: 10.3892/ol.2023.13747 -
Breast Cancer Research and Treatment Apr 2023Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly...
A phase 1 study of veliparib (ABT-888) plus weekly carboplatin and paclitaxel in advanced solid malignancies, with an expansion cohort in triple negative breast cancer (TNBC) (ETCTN 8620).
BACKGROUND
Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC).
METHODS
Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1.
RESULTS
Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%.
CONCLUSION
Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity.
Topics: Humans; Female; Carboplatin; Paclitaxel; Breast Neoplasms; Triple Negative Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Anemia
PubMed: 36853577
DOI: 10.1007/s10549-023-06889-0 -
European Journal of Nuclear Medicine... Jun 2023Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive...
PURPOSE
Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates.
METHODS
We synthesized [C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (V), nondisplaceable volume of distribution (V), and nondisplaceable binding potential (BP) in selected brain regions.
RESULTS
[C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85 MBq/nmol (n = 6). [C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5 mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BP > 3) and low nonspecific uptake (V < 3 mL/cm) in the monkey brain.
CONCLUSION
[C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [C]PyBic to have broad applications in oncology and neuroimaging.
Topics: Rats; Animals; Glioblastoma; Poly(ADP-ribose) Polymerase Inhibitors; Tissue Distribution; Brain; Positron-Emission Tomography; Primates
PubMed: 36849748
DOI: 10.1007/s00259-023-06162-y -
Biomedicines Jan 2023Despite the options available for breast cancer (BC) therapy, several adverse effects and resistance limit the success of the treatment. Furthermore, the use of a single... (Review)
Review
Despite the options available for breast cancer (BC) therapy, several adverse effects and resistance limit the success of the treatment. Furthermore, the use of a single drug is associated with a high failure rate. We investigated through a systematic review the in vitro effects of the combination between conventional drugs and bioactive compounds derived from cinnamic acid in BC treatment. The information was acquired from the following databases: PubMed, Web of Science, Embase, Scopus, Lilacs and Cochrane library. We focused on "Cinnamates", "Drug Combinations" and "Breast neoplasms" for publications dating between January 2012 and December 2022, based on the PRISMA statement. The references of the articles were carefully reviewed. Finally, nine eligible studies were included. The majority of these studies were performed using MCF-7, MDA-MB-231, MDA-MB-468 and BT-20 cell lines and the combination between cisplatin, paclitaxel, doxorubicin, tamoxifen, dactolisib and veliparib, with caffeic acid phenethyl ester, eugenol, 3-caffeoylquinic acid, salvianolic acid A, ferulic acid, caffeic acid, rosmarinic acid and ursolic acid. The combination improved overall conventional drug effects, with increased cytotoxicity, antimigratory effect and reversing resistance. Combining conventional drugs with bioactive compounds derived from cinnamic acid could emerge as a privileged scaffold for establishing new treatment options for different BC types.
PubMed: 36830811
DOI: 10.3390/biomedicines11020275 -
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