ADP-ribose Research Articles

18F]Fluorthanatrace PET in Ovarian Cancer: Comparison with [18F]FDG PET, Lesion Location, Tumor Grade, and Breast Cancer Gene Mutation Status.

Poly(adenosine diphosphate-ribose) polymerase-1 (PARP1) inhibitors have improved ovarian cancer treatment outcomes. However, clinical response remains heterogeneous. Existing biomarkers, mainly breast cancer susceptibility genes 1 and 2 (BRCA1/2), are suboptimal. New tools are needed to guide patient selection. In this study, [18F]fluorthanatrace ([18F]FTT), a PET radiotracer for imaging PARP1, was compared with [18F]FDG and tumor features commonly assessed in ovarian cancer. Methods: Subjects with epithelial ovarian cancer underwent both [18F]FTT and [18F]FDG PET before new oncologic treatment. The SUVmax of [18F]FTT and [18F]FDG was compared between lesions. [18F]FTT SUVmax was compared with tumor location, tumor grade, and germline or somatic BRCA1/2 status. Linear mixed models were fitted to identify subject-level differences. Results: Fifty-five lesions were identified in 14 subjects. No correlation was found between [18F]FTT SUVmax and [18F]FDG SUVmax per lesion, supporting distinct molecular targets. [18F]FTT uptake varied widely across lesions, with no significant differences between mean SUVmax and tumor location, grade, or BRCA1/2 status. Conclusion: Our findings suggest that [18F]FTT PET may provide unique information on ovarian cancer distinct from [18F]FDG PET and commonly assessed tumor features. Our results imply a wide range of PARP1 expression in the studied ovarian tumors not explained by [18F]FDG PET, location, grade, or mutational status.

Therapeutic targeting of the oxidative stress generated by pathological molecular pathways in the neurodegenerative diseases, ALS and Huntington's.

Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models.

Therapy-related myeloid neoplasms in Korean patients with ovarian or primary peritoneal cancer treated with poly(ADP-ribose) polymerase inhibitors.

Prior prospective studies have demonstrated the efficacy of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPis) in various cancers with mutations in the breast cancer gene (BRCA), such as ovarian and breast cancers. However, PARPi have also been associated with an increased incidence of therapy-related myeloid neoplasms (t-MNs). This study aimed to investigate the incidence of t-MNs following PARPi therapy in patients with ovarian or primary peritoneal cancer in Korea and to identify related risk factors. We retrospectively analyzed data of patients with ovarian or primary peritoneal cancer who received PARPi therapy between January 2015 and June 2023. Among 52 patients treated with PARPi, four were diagnosed with t-MNs. All four patients had BRCA mutations, and two of them had breast cancer with no evidence of disease (NED) status following treatment. All patients received radiotherapy and at least one granulocyte-colony stimulating factor (G-CSF) application. The median duration of PARPi therapy was 16.3 (range, 6.2-48.8) months. At the time of analysis, three patients had metastatic ovarian cancer and one maintained the NED status. Next-generation sequencing (NGS) performed in four patients revealed TP53 mutations and complex karyotypes in all tested patients. Among the four patients, three received only supportive care, and one was actively undergoing t-MN treatment. The incidence of t-MNs after PARPi therapy in the current study was higher than that of overall t-MNs, which is consistent with the results of previous studies on t-MNs after PARPi therapy. Further international studies are needed to elucidate the mechanism and clinical characteristics of t-MNs associated with PARPi therapy.

Talazoparib for the Treatment of Metastatic Castration-resistant Prostate Cancer

Breast and prostate cancer are among the most commonly diagnosed cancers worldwide. Recent advances in tumor sequencing and gene studies have led to a paradigm shift from treatment centered on the type of tumor to therapy more focused on specific immune phenotype markers and molecular alterations. In this review, we discuss the utility and function of talazoparib concerning prostate cancer treatment and summarize recent and planned clinical trials on talazoparib. We searched medical databases for articles relating to the use of talazoparib in prostate cancer from inception. Poly ADP ribose polymerase (PARP) is a family of 17 necessary DNA repair enzymes responsible for base excision repair, single-strand break repair, and double-strand break repair. PARP inhibitors are a class of oral targeted therapies that compete for the NAD+ binding site on PARP molecules. Talazoparib, a potent PARP inhibitor, has emerged as a significant therapeutic option in the treatment of metastatic castration-resistant prostate cancer (mCRPC), particularly for patients with specific genetic alterations. Its role as a PARP inhibitor makes it a targeted therapy, focusing on cancer cells with DNA repair deficiencies. Talazoparib’s role as a biomarker-directed therapy in advanced prostate cancer has been increasingly recognized. The TALAPRO-1 demonstrated durable antitumor activity in mCRPC patients. TALAPRO-2 is a notable clinical trial, specifically examining the effectiveness of Talazoparib when used in combination therapies. Current investigations demonstrate a significant improvement in survival outcomes for the patients of mCRPC, making Talazoparib a promising intervention.

ClickGen: Directed exploration of synthesizable chemical space via modular reactions and reinforcement learning

Despite the significant potential of generative models, low synthesizability of many generated molecules limits their real-world applications. In response to this issue, we develop ClickGen, a deep learning model that utilizes modular reactions like click chemistry to assemble molecules and incorporates reinforcement learning along with inpainting technique to ensure that the proposed molecules display high diversity, novelty and strong binding tendency. ClickGen demonstrates superior performance over the other reaction-based generative models in terms of novelty, synthesizability, and docking conformation similarity for existing binders targeting the three proteins. We then proceeded to conduct wet-lab validation on the ClickGen’s proposed molecules for poly adenosine diphosphate-ribose polymerase 1. Due to the guaranteed high synthesizability and model-generated synthetic routes for reference, we successfully produced and tested the bioactivity of these novel compounds in just 20 days, much faster than typically expected time frame when handling sufficiently novel molecules. In bioactivity assays, two lead compounds demonstrated superior anti-proliferative efficacy against cancer cell lines, low toxicity, and nanomolar-level inhibitory activity to PARP1. We demonstrate that ClickGen and related models may represent a new paradigm in molecular generation, bringing AI-driven, automated experimentation and closed-loop molecular design closer to realization.

Phase 2 Trial of Veliparib, Local Irradiation and Temozolomide in Patients with Newly Diagnosed High-Grade Glioma: A Children's Oncology Group Study.

The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral poly(adenosine diphosphate-ribose) polymerase (PARP) 1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy. We conducted a single-arm, non-randomized phase 2 clinical trial to determine whether treatment with veliparib and radiotherapy, followed by veliparib and temozolomide, improves progression-free survival in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features. Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant). Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year event-free survival (EFS) was 23% (standard error, SE = 9%) and 1-year overall survival (OS) was 64% (SE = 10%). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year EFS was 57% (SE = 13%) and 1-year OS was 93% (SE = 0.7%). Rapid central pathology review and molecular testing for eligibility was feasible. The protocol therapy including radiation, veliparib and temozolomide was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts treated with higher doses of alkylator chemotherapy.

Efficacy and safety of angiogenesis inhibitors combined with poly ADP ribose polymerase inhibitors in the maintenance treatment of advanced ovarian cancer: a meta-analysis.

This meta-analysis was performed to evaluate the efficacy and safety of angiogenesis inhibitors (Ais) combined with poly ADP ribose polymerase inhibitors (PARPi) in the maintenance treatment of advanced ovarian cancer (OC). A systematic search was conducted in four databases (Pubmed, Embase, Web of Science, and Cochrane) for articles published from the inception of the databases until January 15, 2024. The focus of the search was on articles investigating the combination of Ais with PARPi in the maintenance treatment of ovarian cancer. Meta-analyses were conducted to assess the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the risk of Grade ≥ 3 adverse events (Grade≥ 3 AEs). Totally nine studies were included for meta-analysis. The overall pooled ORR of Ais combined with PARPi was 57% (95% CI, 35% to 77%). Subgroup analyses showed that the ORR for patients with platinum-resistant recurrent ovarian cancer, platinum-sensitive recurrent ovarian cancer and newly diagnosed advanced ovarian cancer were 30% (95% CI, 12% to 52%), 70% (95% CI, 61% to 78%) and 59% (95% CI, 55% to 63%), respectively. The median PFS was 5.8 months (95% CI, 5.3 to 7.1), 12.4 months (95% CI, 10.6 to 13.2) and 22.4 months (95% CI, 21.5 to 24.2), respectively. The median OS was 15.5 months (95% CI, 12.3 to 24.8), 40.8 months (95% CI, 33.4 to 45.2) and 56.3 months (95% CI, 49.0 to 62.0), respectively. The rate Grade≥ 3 TRAEs rate was found to be 0.22 (95% CI, 0.13 to 0.33). Our results confirmed that PARPi plus Ais was a feasible and safeoption for the maintenance treatment of advanced ovarian cancer. Thecombination therapy should be recommended as the first-line maintenance treatment for patients with advanced ovarian cancer. PARPi plus Ais yielded more favorable oncological prognosis for patients with platinum-sensitive recurrent ovarian cancer, compared to patients with platinum-resistant recurrent ovarian cancer. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024543590, identifier CRD42024543590.

Olaparib-induced myelodysplasia – A case report

Olaparib is an antineoplastic agent that is a poly ADP ribose polymerase (PARP) inhibitor and is Food and Drug Administration-approved for the treatment of ovarian, breast, pancreatic, and prostate cancer. PARP inhibitors can cause DNA damage and epigenetic changes, leading to hematological transformations and increasing the risk of myelodysplasia. We present a case of a 58-year-old female with malignant breast cancer initiated on Olaparib after failing multiple treatment lines. The patient had persistent declining blood cell counts, and a bone marrow biopsy revealed hypercellular bone marrow with predominant myeloid cells with increasing number of blasts and promyelocytes. Olaparib was stopped. The patient elected for supportive care and hospice.

A conserved mechanism couples cytosolic domain movements to pore gating in the TRPM2 channel

Transient Receptor Potential Melastatin 2 (TRPM2) cation channels contribute to immunocyte activation, insulin secretion, and central thermoregulation. TRPM2 opens upon binding cytosolic Ca2+ and ADP ribose (ADPR). We present here the 2.5 Å cryo-electronmicroscopy structure of TRPM2 from Nematostella vectensis (nvTRPM2) in a lipid nanodisc, complexed with Ca2+ and ADPR-2'-phosphate. Comparison with nvTRPM2 without nucleotide reveals that nucleotide binding-induced movements in the protein's three "core" layers deconvolve into a set of rigid-body rotations conserved from cnidarians to man. By covalently crosslinking engineered cysteine pairs we systematically trap the cytosolic layers in specific conformations and study effects on gate opening/closure. The data show that nucleotide binding in Layer 3 disrupts inhibitory intersubunit interactions, allowing rotation of Layer 2 which in turn expands the gate located in Layer 1. Channels trapped in that "activated" state are no longer nucleotide dependent, but are opened by binding of Ca2+ alone.

The Phase 3 KEYLYNK-006 Study of Pembrolizumab Plus Olaparib Versus Pembrolizumab Plus Pemetrexed as Maintenance Therapy for Metastatic Nonsquamous NSCLC

IntroductionPoly (adenosine diphosphate–ribose) inhibitors, including olaparib, upregulate programmed cell death ligand 1, which may increase the efficacy of anti–programmed cell death ligand 1 therapies. MethodsIn the phase 3 KEYLYNK-006 trial (NCT03976323), eligible adults with previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations who had complete response, partial response, or stable disease after induction therapy with four cycles of pembrolizumab 200 mg every three weeks, pemetrexed 500 mg/m2, and carboplatin AUC5 or cisplatin 75 mg/m2 were randomized in a one-to-one ratio to olaparib 300 mg orally twice daily or pemetrexed every three weeks, both given with 31 cycles or less of pembrolizumab every three weeks. Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). Progression-free survival was tested at interim analysis 2 (i.e., final PFS analysis) and OS at final analysis (FA). ResultsOf 1003 patients who received induction therapy, 672 (67.0%) were randomized to pembrolizumab plus olaparib (n = 337) or pembrolizumab plus pemetrexed (n = 335) in the intention-to-treat population. Median follow-up at FA was 39.9 (range: 28.1–51.5) months. At interim analysis 2, the median (95% confidence interval [CI]) PFS was 7.1 (5.6–8.7) months versus 8.3 (6.9–11.5) months in the olaparib versus pemetrexed groups (hazard ratio = 1.12, 95% CI: 0.92–1.36, p = 0.87). At FA, the median (95% CI) OS was 20.7 (18.0–24.8) months versus 23.0 (19.0–26.4) months (hazard ratio = 1.04, 95% CI: 0.87–1.25, p = 0.6649). Grade 3 to 5 maintenance treatment-related adverse events occurred in 26.1% versus 30.1% of patients, respectively. ConclusionPembrolizumab plus maintenance olaparib did not improve PFS or OS versus pembrolizumab plus pemetrexed in previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations.

Phase II Randomized Study of Maintenance Atezolizumab Versus Atezolizumab Plus Talazoparib in Patients With SLFN11 Positive Extensive-Stage SCLC: S1929

ObjectiveTo evaluate whether the addition of a poly (adenosine diphosphate–ribose) polymerase inhibitor talazoparib to maintenance immune checkpoint inhibitor atezolizumab after frontline chemoimmunotherapy improved outcomes in patients with Schlafen 11 (SLFN11)-positive extensive-stage SCLC (ES-SCLC). MethodsPatients with newly diagnosed SLFN11 expressing (H-score ≥ 1, evaluated centrally) ES-SCLC were randomized to maintenance atezolizumab (A) versus atezolizumab plus talazoparib (AT) after frontline chemotherapy plus atezolizumab. The primary objective was to compare progression-free survival (PFS) using a one-sided 10% level stratified log-rank test. Secondary endpoints included objective response rate, overall survival, and toxicity. The target sample size was 84 eligible patients. ResultsFrom June 15, 2020, to December 15, 2022, 106 eligible patients were randomized (54 to AT and 52 to A). Progression-free survival was improved with AT versus A (hazard ratio = 0.66, 80% confidence interval: 0.50–0.86, one-sided p = 0.019) with a median PFS of 2.9 and 2.4 months; overall survival was not different between groups (hazard ratio = 0.98, 80% confidence interval: 0.71–1.36, one-sided p = 0.47). Grade 3 and higher non-hematologic treatment-related adverse events occurred in 17% of patients with AT and 14% of patients with A. Grade 3 and higher hematological treatment-related adverse events were more common in AT (50%) than in A (4%) (p < 0.001). ConclusionMaintenance AT improved PFS in patients with SLFN11-positive ES-SCLC that did not progress after initial chemo-immunotherapy. Hematologic toxicity, primarily grade 3 anemia, was increased with AT, as expected. Prospective biomarker selection was demonstrated, paving the way for future evaluation of novel therapies in molecularly defined SCLC populations.

Use of DNA methyltransferase inhibitor and poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) in the treatment of PARPi-resistant, high-grade serous ovarian cancer

Use of DNA methyltransferase inhibitor and poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) in the treatment of PARPi-resistant, high-grade serous ovarian cancer

Kinetic Analysis and Metabolism of Poly(Adenosine Diphosphate-Ribose) Polymerase-1-Targeted 18F-Fluorthanatrace PET in Breast Cancer.

The poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have demonstrated efficacy in ovarian, breast, and prostate cancers, but current biomarkers do not consistently predict clinical benefit. 18F-fluorthanatrace (18F-FTT) is an analog to rucaparib, a clinically approved PARPi, and is a candidate biomarker for PARPi response. This study intends to characterize 18F-FTT pharmacokinetics in breast cancer and optimize image timing for clinical trials. A secondary aim is to determine whether 18F-FTT uptake in breast cancer correlates with matched frozen surgical specimens as a reference standard for PARP-1 protein. Methods: Thirty prospectively enrolled women with a new diagnosis of breast cancer were injected with 18F-FTT and imaged dynamically 0-60 min after injection over the chest, with an optional static scan over multiple bed positions starting around 70 min. Kinetic analysis of lesion uptake was performed using blood-pool activity with population radiometabolite corrections. Normal breast and normal muscle reference tissue models were compared with PARP-1 protein expression in 10 patients with available tissue. Plasma radiometabolite concentrations and uptake in tumor and normal muscle were investigated in mouse xenografts. Results: Pharmacokinetics of 18F-FTT were well fit by Logan plot reference region models of reversible binding. However, fits of 2-tissue compartment models assuming negligible metabolite uptake were unstable. Rapid metabolism of 18F-FTT was demonstrated in mice, and similar uptake of radiometabolites was found in tumor xenografts and normal muscle. Tumor 18F-FTT distribution volume ratios relative to normal muscle reference tissue correlated with tissue PARP-1 expression (P < 0.02, n = 10). The tumor-to-normal muscle ratio from a 5-min frame between 50 and 60 min after injection, a potential static scan protocol, closely corresponded to the distribution volume ratio relative to normal muscle and correlated to PARP-1 expression (P < 0.02, n = 10). Conclusion: This study of PARPi analog 18F-FTT showed that uptake kinetics invivo corresponded to expression of PARP-1 and that 18F-FTT quantitation is influenced by radiometabolites that are increasingly present late after injection. Radiometabolites can be controlled by using optimal image acquisition timing or normal muscle reference tissue modeling in dynamic imaging or a tumor-to-normal muscle ratio. Optimal image timing for tumor-to-normal muscle quantification in humans appears to be between 50 and 60 min after injection. Therefore, a clinically practical static imaging protocol commencing 45-55 min after injection may sufficiently balance 18F-FTT uptake with background clearance and radiometabolite interference for quantitative interpretation of PARP-1 expression invivo.

Multi-omics landscape and molecular basis of radiation tolerance in a tardigrade.

Tardigrades are captivating organisms known for their resilience in extreme environments, including ultra-high-dose radiation, but the underlying mechanisms of this resilience remain largely unknown. Using genome, transcriptome, and proteome analysis of Hypsibius henanensis sp. nov., we explored the molecular basis contributing to radiotolerance in this organism. A putatively horizontally transferred gene, DOPA dioxygenase 1 (DODA1), responds to radiation and confers radiotolerance by synthesizing betalains-a type of plant pigment with free radical-scavenging properties. A tardigrade-specific radiation-induced disordered protein, TRID1, facilitates DNA damage repair through a mechanism involving phase separation. Two mitochondrial respiratory chain complex assembly proteins, BCS1 and NDUFB8, accumulate to accelerate nicotinamide adenine dinucleotide (NAD+) regeneration for poly(adenosine diphosphate-ribosyl)ation (PARylation) and subsequent poly(adenosine diphosphate-ribose) polymerase 1 (PARP1)-mediated DNA damage repair. These three observations expand our understanding of mechanisms of tardigrade radiotolerance.

Comparison of adverse events of poly adenosine diphosphate ribose polymerase inhibitors in patients with ovarian cancer using the United States Food and Drug Administration Adverse Event Reporting System

ABSTRACT Background Olaparib, niraparib, and rucaparib are the three primary poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors that are currently available in the market. Previous studies indicate different incidences of adverse events based on the PARP inhibitor or country. Research design and methods This study used data from the United States Food and Drug Administration Adverse Event Reporting System collected between January 2018 and December 2023. The data analyzed in this study involved patients receiving PARP inhibitors for treating ovarian cancer. A comparative analysis of the three PARP inhibitors was conducted using the reporting odds ratio (ROR) and the adjusted ROR (aROR) controlling for patient background differences. Results The aROR for niraparib was significant at > 1.000, including platelet count decreased (p < 0.001) and thrombocytopenia (p < 0.001) when olaparib was set as the reference. Conversely, the aROR for niraparib was significant at < 1.000, including anemia (p < 0.001). Additionally, significant differences were observed in various adverse events for rucaparib. Moreover, significant differences were observed when comparing between countries. Conclusions This study indicates that the types of adverse events may vary by PARP inhibitor and by country. These results will be beneficial in clinical practice.

Inhibition of Chk1 with Prexasertib Enhances the Anticancer Activity of Ciclopirox in Non-Small Cell Lung Cancer Cells.

Lung cancer is a leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent lung cancer subtype. Ciclopirox olamine (CPX), an off-patent fungicide, has been identified as a new anticancer agent. Prexasertib (PRE), a Chk1 inhibitor, is in phase 1/2 clinical trials in various tumors. The anticancer effect of the combination of CPX with PRE on NSCLC cells is unknown. Here, we show that CPX is synergistic with PRE in inhibiting cell proliferation and inducing apoptosis of NSCLC (A549 and A427) cells. Combined treatment with CPX and PRE significantly increased the cell population in the G1/G0 and sub-G1 phases, compared to the single treatment with CPX or PRE. Concurrently, the combined treatment downregulated the protein levels of cyclins (A, B1), cyclin-dependent kinases 4, 6, 2 (CDK4, CDK6, CDK2), cell division cycle 25 B, C (Cdc25B, Cdc25C), and upregulated the protein levels of the CDK inhibitors p21 and p27, leading to decreased phosphorylation of Rb. In addition, the combined treatment increased DNA damage, evidenced by increased expression of γH2AX. In line with this, the combined treatment induced more apoptosis than either single treatment. This was associated with increased expression of DR4, DR5, Fas, and FADD and decreased expression of survivin, resulting in activation of caspase 8 and caspase 3 as well as cleavage of poly (ADP ribose) polymerase (PARP). Taken together, the results suggest that inhibition of Chk1 with PRE can enhance the anticancer activity of CPX at least partly by decreasing cell proliferation and increasing apoptosis in NSCLC cells.

Neurosurgical application of olaparib from a thermo-responsive paste potentiates DNA damage to prolong survival in malignant glioma

BackgroundThere is increased pan-cancer specific interest in repurposing the poly adenosine diphosphate-ribose polymerase-1 (PARP-1) inhibitor, olaparib, for newly diagnosed or recurrent isocitrate dehydrogenase wild type glioblastoma. We explore whether intra-cavity delivery of olaparib confers a survival benefit in a pre-clinical high-grade glioma model.MethodsPrimary tumor RNA sequencing data was used to determine PARP-1 as a target in the glioblastoma infiltrative margin. We assessed radiosensitization conferred by olaparib alone and concomitant to genotoxic insults in vitro using clonal growth assays, cell cycle analysis and immunocytochemistry, and in vivo upon post-surgical delivery from a temperature-sensitive polymeric paste.ResultsRNA-sequencing confirmed PARP-1 as a viable therapy target in glioblastoma infiltrative disease. Acute exposure of glioma cells to olaparib impaired proliferation and induced late-stage apoptosis associated with DNA damage in vitro, potentiated by radiation. Using high-grade glioma orthotopic allografts, a long-term overall survival benefit was observed upon interstitial olaparib delivery concomitant with radiotherapy, compared to systemic olaparib and standard glioblastoma treatment. Combined delivery of olaparib with either temozolomide or etoposide increased long-term survival, suggestive of olaparib functioning as DNA damage sensitizer.ConclusionsCollectively, our data support a rationale for localized olaparib delivery concomitant with the current clinical regimen for malignant glioma treatment.

PARP Pioneers: Using BRCA1/2 Mutation-targeted Inhibition to Revolutionize Breast Cancer Treatment.

Breast Cancer stands on the second position in the world in being common and women happen to have it with high rate of about five-folds around the world. The causes of occurrence can matter with different humans be it external factors or the internal genetic ones. Breast cancer is primarily driven by mutations in the BRCA1 and BRCA2 susceptibility genes. These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). Poly (ADP ribose) polymerases (PARP) are the essential enzymes involved in the repairing of the damaged DNA. So the inhibition of these inhibitors can be considered as the promising strategy for targeting cancers with defective damage in the deoxyribonucleic acid. Olaparib and talazoparib are PARP inhibitors (PARPi) are being employed for the monotherapies in case of the deleterious germline HER2-negative and BRCA-mutated breast cancer. The potency of PARP for trapping on DNA and causes cytotoxicity may have difference in the safety and efficacy with the PARPi. The PARPi have been found its place in the all different types of Breast Cancers and have shown potential benefits. The purpose of this review is to provide an update on the oral poly(ADP-ribose) polymerase (PARP)inhibitors for the improvement in the treatment and management of Breast Cancer.

Evidence of apoptosis as an early event leading to cyclophosphamide-induced primordial follicle depletion in a prepubertal mouse model.

The mechanisms leading to ovarian primordial follicle depletion following gonadotoxic chemotherapy with cyclophosphamide and other cytotoxic drugs are currently understood through two main explanatory theories: apoptosis and over-activation. Discrepancies between the findings of different studies investigating these mechanisms do not allow to reach a firm conclusion. The heterogeneity of cell types in ovaries and their different degrees of sensitivity to damage, cell-cell interactions, periodical follicle profile differences, model age-dependent differences, and differences of exposure durations of tested drugs may partially explain the discrepancies among studies. This study used intact prepubertal mice ovaries in culture as study model, in which most follicles are primordial follicles. Histological and transcriptional analyses of ovaries exposed to the active metabolite of cyclophosphamide 4-hydroperoxycyclophosphamide (4-HC) were carried out via a time-course experiment at 8, 24, 48, and 72 h. 4-HC treated ovaries showed a significant decrease in primordial follicle density at 24 h, along with active DNA damage (TUNEL) and overexpressed apoptosis signals (cleaved-poly ADP ribose polymerase in immunohistochemistry and western blotting). Meanwhile 4-HC treatment significantly up-regulated H2ax, Casp 6, Casp 8, Noxa, and Bax in ovaries, and up-regulated Puma in primordial follicles (FISH). Our results indicated that cyclophosphamide-induced acute ovarian primordial follicle depletion was mainly related to apoptotic pathways. No evidence of follicle activation was found, neither through changes in the expression of related genes to follicle activation nor in the density of growing follicles. Further validation at protein level in 4-HC-treated prepubertal mice ovaries at 24 h confirmed these observations.

Effect of Preoperative Glucocorticoid Application on Vitreous Parthanatos-Related Protein Expression in Patients with Rhegmatogenous Retinal Detachment Associated with Choroidal Detachment

Purpose The protein concentrations of apoptosis inducing factor (AIF), macrophage migration inhibitory factor (MIF), interleukin-1β (IL-1β), poly ADP ribose polymerase-1 (PARP-1), poly (ADP-ribose) (PAR), α-synuclein (α-SYN), monocyte chemotactic protein‑1 (MCP-1) and tumor necrosis factor-α (TNF-α) in the vitreous of eyes with rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD) were observed and analyzed. Methods A total of 57 patients’ samples were included. 30 patients with RRD were set as the control group, 27 patients with RRDCD were set as the experimental group (16 patients with preoperative glucocorticosteroid (GC+) and 11 patients without preoperative glucocorticosteroid (GC−)). The levels of AIF, MIF, IL-1β, PARP-1, PAR, α-SYN, MCP-1 and TNF-α in vitreous of patients in the control and experimental groups were detected by enzyme-linked immunosorbent assay (ELISA). Results The concentration of AIF in the vitreous was higher in the RRD group (9.96 ± 2.78 ng/ml) than in the RRDCD (GC+) group (7.65 ± 2.13 ng/ml, p = 0.006),the RRDCD (GC+) group was lower than the RRDCD (GC−) group (10.28 ± 2.81 ng/ml) (p = 0.013). The concentration of MIF in vitreous fluid was lower in the RRDCD (GC+) group (61.21 ± 17.56 ng/ml) than in the RRDCD (GC−) group (74.30 ± 9.66 ng/ml, p = 0.039). In the experimental group, the protein concentration of MCP-1 in the RRDCD (GC+) group was higher in the preoperative PVR grading C (284.93 ± 54.96 ng/ml) grade than in the D grade (225.94 ± 24.05 ng/ml) (p = 0.050); The protein concentration of MIF was lower in the RRDCD (GC+) group of patients with an ocular axis of <26 mm (56.19 ± 6.99 ng/ml) than in those with an ocular axis of ≥26 mm (76.26 ± 26.60 ng/ml, p = 0.043). Conclusion Low expression of Parthanatos-related proteins is present in the vitreous of patients with RRDCD (GC+), and preoperative treatment with glucocorticoids may reduce the expression of Parthanatos-related proteins.