Polymerase Inhibitor Olaparib Research Articles

Combined effects of carbon ion radiation and PARP inhibitor on non-small cell lung carcinoma cells: Insights into DNA repair pathways and cell death mechanisms

The utilization of high linear energy transfer (LET) carbon ion (12C-ion) in radiotherapy has witnessed a notable rise in managing highly metastatic, recurrent, and chemo/radio-resistant human cancers. Non-small cell lung cancer (NSCLC) presents a formidable challenge due to its chemo-resistance and aggressive nature, resulting in poor prognosis and survival rates. In a previous study, we demonstrated that the combination of 12C-ion with the poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib significantly mitigated metastasis in A549 cells. Here, we delve into the underlying rationale behind the combined action of olaparib with 12C-ion, focusing on DNA repair pathways and cell death mechanisms in asynchronous NSCLC A549 cells following single and combined treatments. Evaluation included analysis of colony-forming ability, DNA damage assessed by γH2AX foci, expression profiling of key proteins involved in Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ) repair pathways, caspase-3 activation, apoptotic body formation, and autophagic cell death. Our findings reveal that both PARPi olaparib and rucaparib sensitize A549 cells to 12C-ion exposure, with olaparib exhibiting superior sensitization. Moreover, 12C-ion exposure alone significantly downregulates both HR and NHEJ repair pathways by reducing the expression of MRE11--RAD51 and Ku70-Ku80 protein complexes at 24 h post-treatment. Notably, the combination of olaparib pre-treatment with 12C-ion markedly inhibits both HR and NHEJ pathways, culminating in DNA damage-induced apoptotic and autophagic cell death. Thus we are the first to demonstrate that olaparib sensitizes NSCLC cells to carbon ion by interfering with HR and NHEJ pathway. These insights underscore the promising therapeutic potential of combining PARP inhibition with carbon ion exposure for effective NSCLC management.

HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.

10616 Background: Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with BRCA1- or BRCA2- ( BRCA1/2) associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC. Methods: A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in BRCA1/2, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response. Results: Eight treated pts (s BRCA1:1 ;g BRCA2:6; s BRCA2:1 ) had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in >1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in >50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts. Conclusions: MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331 .

Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition.

Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death. We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.

Free drug and ROS-responsive nanoparticle delivery of synergistic doxorubicin and olaparib combinations to triple negative breast cancer models.

Combinations of the topoisomerase II inhibitor doxorubicin and the poly (ADP-ribose) polymerase inhibitor olaparib offer potential drug-drug synergy for the treatment of triple negative breast cancers (TNBC). In this study we performed in vitro screening of combinations of these drugs, administered directly or encapsulated within polymer nanoparticles, in both 2D and in 3D spheroid models of breast cancer. A variety of assays were used to evaluate drug potency, and calculations of combination index (CI) values indicated that synergistic effects of drug combinations occurred in a molar-ratio dependent manner. It is suggested that the mechanisms of synergy were related to enhancement of DNA damage as shown by the level of double-strand DNA breaks, and mechanisms of antagonism associated with mitochondrial mediated cell survival, as indicated by reactive oxygen species (ROS) generation. Enhanced drug delivery and potency was observed with nanoparticle formulations, with a greater extent of doxorubicin localised to cell nuclei as evidenced by microscopy, and higher cytotoxicity at the same time points compared to free drugs. Together, the work presented identifies specific combinations of doxorubicin and olaparib which were most effective in a panel of TNBC cell lines, explores the mechanisms by which these combined agents might act, and shows that formulation of these drug combinations into polymeric nanoparticles at specific ratios conserves synergistic action and enhanced potency in vitro compared to the free drugs.

Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair.

Dysregulation of the DNA damage response may contribute to the sensitization of cancer cells to DNA-targeting agents by impelling cell death. In fact, the inhibition of the DNA repair pathway is considered a promising anticancer therapeutic strategy, particularly in combination with standard-of-care agents. The xanthonoside XGAc was previously described as a potent inhibitor of cancer cell growth. Herein, we explored its antitumor activity against triple-negative breast cancer (TNBC), ovarian cancer and pancreatic ductal adenocarcinoma (PDAC) cells as a single agent and in combination with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib. We demonstrated that XGAc inhibited the growth of TNBC, ovarian and PDAC cells by inducing cell cycle arrest and apoptosis. XGAc also induced genotoxicity, inhibiting the expression of DNA repair proteins particularly involved in homologous recombination, including BRCA1, BRCA2 and RAD51. Moreover, it displayed potent synergistic effects with olaparib in TNBC, ovarian cancer and PDAC cells. Importantly, this growth inhibitory activity of XGAc was further reinforced in a TNBC spheroid model and in patient-derived ovarian cancer cells. Also, drug-resistant cancer cells showed no cross-resistance to XGAc. Additionally, the ability of XGAc to prevent cancer cell migration was evidenced in TNBC, ovarian cancer and PDAC cells. Altogether, these results highlight the great potential of acetylated xanthonosides such as XGAc as promising anticancer agents against hard-to-treat cancers.

Comparative efficacy of olaparib in combination with or without novel antiandrogens for treating metastatic castration-resistant prostate cancer.

Studies using novel antiandrogens (NAA) in patients with metastatic castration-resistant prostate cancer (mCRPC) have shown overall survival benefit. As patients develop resistance to NAA therapy, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib in combination with NAA may become a promising therapy. However the overall benefit of olaparib monotherapy or combination therapy still needs to be evaluated. Therefore, we performed a network meta-analysis to assess the efficacy and toxicity between olaparib, olaparib combined with abiraterone and NAA. We searched PubMed, EMBASE, the Cochrane Library and American Society of Clinical Oncology (ASCO) University Meeting abstracts for randomized controlled trials reporting olaparib and NAA from 2010 up to March, 2023. Network meta-analysis using Stata 16.0 and R 4.4.2, hazard ratios (HR) with 95% confidence intervals (CI) were used to assess the results. Four trials reported olaparib, olaparib plus abiraterone and apalutamide plus abiraterone. radiographic progression-free survival (rPFS) was significantly lower in patients on apalutamide plus abiraterone compared to olaparib (HR, 1.43; 95% CI, 1.06-1.93). rPFS was similar for olaparib plus abiraterone and olaparib (HR, 1.35; 95% CI, 0.99-1.84); likewise, olaparib plus abiraterone and apalutamide plus abiraterone were similar (HR, 1.06; 95% CI, 0.83-1.35). In addition, there was no significant difference between the three interventions for OS. But olaparib has the highest probability of being a preferred treatment for improving rPFS and OS. rPFS was in favor of olaparib compared with apalutamide plus abiraterone. But there were no difference between olaparib plus abiraterone and either olaparib or apalutamide plus abiraterone. Apalutamide plus abiraterone might be the most preferred intervention in cases where AEs are involved. https://inplasy.com, identifier INPLASY2023100072.

OS09.3.A FINAL RESULTS OF THE MGMT UNMETHYLATED ARM OF PARADIGM-2: A PHASE I STUDY OF OLAPARIB AND RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)

Abstract BACKGROUND The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has radio and chemosensitizing effects in preclinical models and penetrates GBM in patients at radiosensitizing concentrations. PARP inhibitors sensitize proliferating cells to temozolomide (TMZ) but exacerbate haematological toxicity. Patients with MGMT unmethylated tumours do not benefit from TMZ so it can be withheld, enabling continuous olaparib dosing with radiotherapy (RT). Patients with MGMT methylated tumours benefit from TMZ so olaparib must be combined with chemoradiation (CRT) in an intermittent, low-dose manner. PARADIGM-2 is a clinical trial comprising two parallel phase I studies of olaparib/RT or olaparib/RT/TMZ in newly diagnosed GBM patients stratified by MGMT status. MATERIAL AND METHODS GBM patients aged <70 with WHO performance status 0-1 were eligible. Tumour tissue underwent central pyrosequencing testing for MGMT promoter methylation. MGMT unmethylated patients received daily oral olaparib throughout RT (60 Gray in 30#) and for four weeks afterwards. MGMT methylated patients received intermittent olaparib during CRT (60 Gray plus TMZ 75mg/m2 daily) and for four weeks after. In both arms, olaparib dose was escalated in a 3 + 3 cohort design. ISRCTN 51253312. RESULTS By January 2023, 24 MGMT methylated patients and 43 MGMT unmethylated patients had been recruited. Dose escalation in MGMT unmethylated patients was completed with no dose-limiting toxicities and the recommended phase II dose (RP2D) of olaparib was established at 300 mg twice daily (the full single agent dose). Maximum tolerated dose was not reached. The RP2D cohort was expanded to 30 patients of whom one was excluded because the diagnosis was revised to anaplastic oligodendroglioma. Median overall survival (OS) of the 42 eligible patients was 14.1 months (80% confidence intervals (CI) 12.2 - 15.9), with 12- and 24-month OS estimates of 64.3% (54.0-72.9) and 16.7% (10.1-24.7) respectively. In the dose expansion cohort, 6 of 29 patients are alive with median follow-up time of 22.9 months. Median OS is 14.2 months (12.2-16.9); 12- and 24-month OS estimates are 69.0% (56.5-78.5) and 24.1% (14.8-34.8) respectively. Updated survival data will be presented at the conference. Dose escalation in MGMT methylated patients continues with the current cohort receiving olaparib 150 mg daily 4 days per week. CONCLUSION Pre-treatment stratification by MGMT status in a phase I study in GBM is feasible and enables optimisation of olaparib dosing and scheduling with RT and TMZ. In MGMT unmethylated patients, olaparib can be combined with RT at the full single agent dose (300 mg twice daily) if TMZ is withheld. Of 29 patients receiving this dose, a quarter have survived more than 2 years. In MGMT methylated patients, olaparib can be safely combined with radical CRT when given at lower doses on an intermittent basis (currently 150 mg four days per week).

Poly(ADP-ribose) Polymerase Inhibitor Olaparib in the Treatment of Ovarian Cancer: A Comprehensive Review of Current Literature

Purpose of the review: This comprehensive review aims to provide a summary of current research on the utilization of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in the treatment of ovarian cancer. The review aims to highlight the key findings from recent clinical trials and assess the potential of olaparib as a targeted therapy for improving the prognosis of ovarian cancer patients.
 Recent findings: Ovarian cancer remains a significant global health concern with high mortality rates. While optimal debulking surgery and platinum-based chemotherapy are the standard treatments, the recurrence rates remain substantial. The emergence of PARP inhibitors, particularly olaparib, has introduced a novel therapeutic approach that targets the genomic instability and DNA repair mechanisms in cancer cells. Notable clinical trials, such as SOLO1, SOLO2, and PAOLA-1, have demonstrated the effectiveness of olaparib in significantly improving progression-free survival, particularly in patients with BRCA mutations or homologous recombination deficiency. Additionally, combination therapies involving olaparib, such as those with bevacizumab or entinostat, have shown promising results.
 Summary: The utilization of olaparib has brought about a paradigm shift in the treatment of ovarian cancer. Notably, it has shown significant improvements in progression-free survival and overall survival, particularly in patients with BRCA mutations or homologous recombination deficiency. The exploration of olaparib through various clinical trials and combination therapies continues to provide valuable insights and offer new prospects for ovarian cancer patients. Moreover, the growing understanding of PARP inhibitors holds the potential for further advancements in the prognosis of patients with this formidable condition.

Maintenance Treatment for Metastatic Pancreatic Cancer: Balancing Therapeutic Intensity with Tolerable Toxicity.

Metastatic pancreatic ductal adenocarcinoma is typically treated with multi-agent chemotherapy until disease progression or intolerable cumulative toxicity. For patients whose disease shows ongoing control or response beyond a certain timeframe (≥3-4 months), options include pausing chemotherapy with close monitoring or de-escalating to maintenance therapy with the goal of prolonging progression-free and overall survival while preserving quality of life. There is currently no universally accepted standard of care and a relative dearth of randomized clinical trials in the maintenance setting. Conceptually, such therapy can entail continuing the least toxic components of a first-line regimen and/or introducing novel agent(s) such as the poly(ADP-ribose) polymerase inhibitor olaparib, which is presently the only approved drug for maintenance treatment and is limited to a genetically defined subset of patients. In addition to identifying new therapeutic candidates and combinations in the maintenance setting, including targeted agents and immunotherapies, future research should focus on better understanding this unique biologic niche and how treatment in the maintenance setting may be distinct from resistant/refractory disease; identifying molecular predictors for more effective pairing of specific treatments with patients most likely to benefit; and establishing patient-reported outcomes in clinical trials to ensure accurate capture of quality of life metrics.

A mathematical model to investigate the effects of ceralasertib and olaparib in targeting the cellular DNA Damage responses pathway.

The ataxia-telangiectasia and Rad3-related (ATR) inhibitor ceralasertib and the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib have shown synergistic activity, in vitro, in the FaDu ATM-KO cell line. It was found that combining these drugs with lower doses and for shorter treatment periods induced greater or equal toxicity in cancer cells than using either as a single agent. Here, we develop a biologically-motivated mathematical model governed by a set of ordinary differential equations, considering the cell cycle-specific interactions of olaparib and ceralasertib. By exploring a range of different possible drug mechanisms, we have studied the effects of their combination as well as which drug interactions are the most prominent. After careful model selection, the model was calibrated and compared to relevant experimental data. We have used this developed model further to investigate other doses of olaparib and ceralasertib in combination, which can be potentially helpful in exploring optimised dosage and delivery. Significance Statement Drugs that target cellular DNA damage repair pathways are now being used as new ways to maximise the effect of multimodality treatments such as radiotherapy. Here, we develop a mathematical model to investigate the effects of ceralasertib and olaparib, two drugs that target DNA damage response pathways.

In brief: A new prostate cancer indication for olaparib (Lynparza).

The oral poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza – AstraZeneca) has now been approved by the FDA for use in combination with abiraterone (Zytiga, and others) and either prednisone or prednisolone for treatment of adults with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC).

Printed cisplatin on microneedle arrays for transdermal delivery enhances olaparib-induced synthetic lethality in a mouse model of homologous recombination deficiency

Small molecule inhibitors targeting specific proteins are claiming a continuously growing share in cancer therapy, more commonly in combination with traditional chemotherapeutic drugs. While these inhibitors are taken orally, the majority of chemotherapies are administered through intravenous injection in the hospital premises. Alternative routes for chemotherapy administration would allow more frequent administration at lower dosing by the patient oneself, allowing combination treatment with reduced side effects. Here, we employed laser printing to prepare microneedles for transdermal delivery of cisplatin. Combination treatment with cisplatin transdermally and the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib orally leads to effective treatment in a cancer xenograft mouse model in vivo, while reducing the risk for systemic side effects. This work opens new avenues in anti-cancer therapy by allowing the administration of chemotherapy without the need for intravenous injection alone or in combination with other therapies.

Radiation in Combination with Immune Checkpoint Blockade and DNA Damage Response Inhibitors in Mice: Dosage Optimization in MC38 Syngeneic Tumors via Modelling and Simulation.

Clinical trials assessing the impact of radiotherapy (RT) in combination with DNA damage response pathway inhibitors (DDRis) and/or immune checkpoint blockade are currently ongoing. However, current methods for optimizing dosage and schedule are limited. A mathematical model was developed to capture the impacts of RT in combination with DDRi and/or anti-PD-L1 [immune checkpoint inhibitor (ICI)] on tumor immune interactions in the MC38 syngeneic tumor model. The model was fitted to datasets that assessed the impact of RT in combination with the DNA protein kinase inhibitor (DNAPKi) AZD7648. The model was further fitted to datasets from studies that were used to assess both RT/ICI combinations as well as RT/ICI combinations followed by concurrent administration of the poly ADP ribose polymerase inhibitor (PARPi) olaparib. Nonlinear mixed-effects modeling was performed followed by internal validation with visual predictive checks (VPC). Simulations of alternative dosage regimens and scheduling were performed to identify optimal candidate dosage regimens of RT/DNAPKi and RT/PARPi/ICI. Model fits and VPCs confirmed a successful internal validation for both datasets and demonstrated very small differences in the median, lower, and upper percentile values of tumor diameters between RT/ICI and RT/PARPi/ICI, which indicated that the triple combination of RT/PARPi/ICI at the given dosage and schedule does not provide additional benefit compared with ICI in combination with RT. Simulation of alternative dosage regimens indicated that lowering the dosage of ICI to between 2 and 4 mg/kg could induce similar benefits to the full dosage regimen, which could be of translational benefit. SIGNIFICANCE STATEMENT: This work provides a mixed-effects model framework to quantify the effects of combination radiotherapy/DNA damage response pathway inhibitors/immune checkpoint inhibitors in preclinical tumor models and identify optimal dosage regimens, which could be of translational benefit.

Harnessing olaparib, palbociclib, and endocrine therapy: A phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA mutation-associated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (HOPE).

TPS1126 Background: Hormone receptor-positive (HR+) metastatic breast cancer (MBC) in patients (pts) with germline or somatic BRCA1 or BRCA2 (g/s BRCA1/2) mutations has dual drivers: hormone receptor signaling and homologous recombination deficiency. The PALOMA-3 trial showed superiority of fulvestrant (F) with palbociclib (P) compared to F alone. The OlympiAD trial showed the poly-ADP ribose polymerase inhibitor (PARPi) olaparib (O) to be superior to chemotherapy in BRCA1/2-associated MBC. However, treatment resistance inevitably develops; targeting dual therapeutic drivers concurrently may delay or circumvent resistance. O and P have overlapping hematologic toxicity and the safety of combined O, P and F is unknown. The tolerability of O + P is particularly relevant given the emergence of potentially less myelosuppressive PARPi. Methods: HOPE (NCT03685331) is a phase I/II trial to evaluate safety and efficacy of O, P and F in pts with g/s BRCA1/2-associated, HR+ MBC. Eligible pts have an ECOG performance status 0-1, measurable/evaluable breast cancer, any/no prior endocrine therapy, and 0-2 lines of chemotherapy for MBC. Prior platinum is allowed for curative intent if completed at least 12 months prior to MBC diagnosis, or for MBC if no progression during therapy. Prior PARPi and CDK4/6i are permitted on phase I, and are permitted during phase II if there was no progression on them. Treatment (28-day cycles) consists of: O orally twice daily continuously; F 500mg intramuscularly on day 1 of each cycle plus load; and P orally once daily on days 1-21. Phase I begins with a 28-day safety run-in of O and F alone. O and P doses are based on dose level (DL): DL 0 (starting level), O 300mg, P 75mg; DL 1, O 300mg, P 100mg; DL 2, O 300mg, P 125mg; DL-1, O 250mg, P 75mg and DL-2, O 200mg, P 75mg. For phase II, O and P will be dosed at MTD. Pts have tissue collection at baseline and peripheral blood cfDNA analysis at baseline, at progression, and at all scan timepoints (every 3 cycles). Phase I primary endpoint is MTD. A 3+3 dose escalation design is used with a 30% rate of dose limiting toxicity (DLT) deemed acceptable, and 6 patients treated at a dose for it to be declared MTD. A minimum of 2 and a maximum of 18 patients will be enrolled on the phase I. Phase II primary endpoint is PFS using Kaplan-Meier methods and secondary efficacy endpoints are objective response rate and 24-week clinical benefit rate. Phase II will evaluate 54 subjects to provide 80% power to detect an increase in PFS from 7 months with O monotherapy to 10 months. Exploratory objectives include examination of baseline tissue for PARPi predictive biomarkers and measures of tumor immunogenicity as well as serial serum evaluation for reversion mutations. Enrollment is ongoing. Clinical trial information: NCT03685331 .

P38 MAPK inhibitor SB203580 enhances anticancer activity of PARP inhibitor olaparib in a synergistic way on non-small cell lung carcinoma A549 cells

The Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib gives promising results against various types of cancers in clinical trials. The combination of drugs always increases therapeutic efficacy because of targeting multiple pathways of cancer progression. Our objective was to explore the potential synergistic anticancer activities of olaparib combined with p38 MAPK inhibitor (MAPKi) SB203580 on non-small cell lung carcinoma (NSCLC) A549 cells. The effects of the individual compound and their combination on cell survival, DNA damage as detected by γH2AX foci, expression of key proteins in Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ) repair, caspase 3 activation, nuclear fragmentation and telomerase regulation were studied in A549 cells. The results showed that olaparib and SB203580 individually reduced cell viability in a dose-dependent manner but combined treatment synergistically reduced cell viability. Olaparib combined with SB203580 significantly reduced error-free HR repair via reducing MRE11-RAD50 and promoted error-prone NHEJ repair by increasing Ku70-Ku80 leading to increased DNA damage-induced apoptosis. Notably, the alteration of proteins in HR/NHEJ pathways, DNA damage and induction of apoptosis was significant by combined treatment but not by 1 μM olaparib treatment alone. In addition, combined treatment reduced telomerase activity more than single treatment via reducing telomerase subunits. These data implicated that the anticancer potential of olaparib was significantly increased by combining SB203580 through increasing DNA damage-induced apoptosis and inhibiting telomerase activity.

First report for the electrochemical determination and proposed mechanism of poly(ADP ribose) polymerase inhibitor and new smart anticancer drug olaparib

First report for the electrochemical determination and proposed mechanism of poly(ADP ribose) polymerase inhibitor and new smart anticancer drug olaparib

Multifunctional biomimetic nanoplatform based on photodynamic therapy and DNA repair intervention for the synergistic treatment of breast cancer.

Photodynamic therapy (PDT) is a minimally invasive and locally effective treatment method, which has been used in the clinical treatment of a variety of superficial tumors. In recent years, PDT has received extensive attention due to its induction of immunogenic cell death (ICD). However, the repair mechanism of tumor cells and low immune response limit the further development of PDT. To this end, a multifunctional biomimetic nanoplatform 4T1Mem@PGA-Ce6/Ola (MPCO) is developed to co-deliver the photosensitizer Chlorin e6 (Ce6) and Olaparib (Ola) with the function of preventing DNA repair. The nanoplatform shows efficient tumor targeting and cellular internalization properties due to cell membrane camouflage, and Ce6 and Ola produce a significant synergistic anti-tumor effect under laser irradiation. Meanwhile, the nanoplatform can also activate the cyclic guanosine monophosphate-adenosine monophosphate synthase-interferon gene stimulator signaling (cGAS-STING) pathway to produce cytokines. The damage-associated molecular patterns induced by ICD can work with these cytokines to recruit and stimulate the maturation of dendritic cells and induce the systemic anti-tumor immune response. Overall, this multifunctional biomimetic nanoplatform integrating PDT, chemotherapy, and immunotherapy is highlighted here to boost anti-tumor therapy. STATEMENT OF SIGNIFICANCE: Self-repair of DNA damage is the most important reason for the failure of primary tumor eradication and the formation of secondary and metastatic tumors. To address this issue, a multifunctional biomimetic nanoplatform 4T1Mem@PGA-Ce6/Ola (MPCO) was developed to integrate a photosensitizer Chlorine a6 and a poly (ADP-ribose) polymerase inhibitor Olaparib. With tumor targeting ability and controlled release of drugs, the MPCO was expected to enhance tumor immunogenicity and facilitate antitumor immunity through the induction of immunogenic cell death as well as the activation of the cGAS-STING pathway. This study develops a promising combination strategy against tumors and has substantial implications for the prognosis of patients with breast cancer.

The Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo

IntroductionOvarian cancer (OC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical efficacy of the Poly (ADP-ribose) polymerase (PARP) inhibitor (olaparib) and the pan-ErbB inhibitor (neratinib) as single agents and in combination in ovarian cancer cell lines and xenografts with variable HER2 expression. MethodsIn vitro cell viability with olaparib, neratinib, and their combination was assessed using flow-cytometry based assays against a panel of OC primary cell lines with variable HER2 expression. Immunoblotting experiments were performed to elucidate the mechanism of activity and synergism. The in vivo antitumor activity of the olaparib/neratinib combination versus single agents was tested in HER2 positive xenograft OC models. ResultsHER2 + OC cell lines demonstrated higher sensitivity to olaparib and neratinib when compared to HER2 negative tumors (i.e., IC50: 2.06 ± 0.33 μM vs. 39.28 ± 30.51 μM, p = 0.0035 for olaparib and 19.42 ± 2.63 nM vs. 235.0 ± 165.0 nM, p = 0.0035 for neratinib). The combination of olaparib with neratinib was more potent when compared to single-agent olaparib or neratinib both in vitro and in vivo, and demonstrated synergy in all primary HER2 + OC models. Western blot experiments showed neratinib decreased pHER2/neu while increased Poly(ADP-ribose) (PAR) enzymatic activity; olaparib increased pHER2/Neu expression and blocked PAR activatio. Olaparib/neratinib in combination decreased both pHER2/Neu as well as PAR activation. ConclusionThe combination of olaparib and neratinib is synergistic and endowed with remarkable preclinical activity against HER2+ ovarian cancers. This combination may represent a novel therapeutic option for ovarian cancer patients with HER2+, homologous recombination-proficient tumors resistant to chemotherapy.

Germline BRCA testing in pancreatic cancer: improving awareness, timing, turnaround, and uptake.

Prognosis is generally poor for patients with pancreatic ductal adenocarcinoma. However, patients with germline BRCA1 or BRCA2 mutations (gBRCAm) may benefit from first-line platinum-based chemotherapy and maintenance therapy with the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib following at least 16 weeks of first-line platinum-based chemotherapy without disease progression. Germline breast cancer gene (BRCA) testing is therefore important to ensure that patients receive the most effective treatment. In addition, testing for other DNA damage response gene mutations beyond gBRCAm may also guide treatment decisions. However, clinical pathways for genetic testing are often suboptimal, leading to delays in treatment initiation or missed opportunities for personalized therapy. Barriers to testing include low rates of referral and uptake, delays to referral and slow result turnaround times, cost, and biopsy and assay limitations if somatic testing is performed, leading to the requirement for subsequent dedicated germline testing. Low rates of referral may result from lack of awareness among physicians of the clinical value of testing, coupled with low confidence in interpreting test results and poor availability of genetic counseling services. Among patients, barriers to uptake may include similar lack of awareness of the clinical value of testing, anxiety regarding the implications of test results, lack of insurance coverage, fear of negative insurance implications, and socioeconomic factors. Potential solutions include innovative approaches to testing pathways, including 'mainstreaming' of testing in which BRCA tests are routinely arranged by the treating oncologist, with the involvement of genetic counselors if a patient is found to have a gBRCAm. More recently, the utility of multigene panel analyses has also been explored. Access to genetic counseling may also be improved through initiatives such as having a genetic counseling appointment for all new patient visits and telemedicine approaches, including the use of telephone consultations or DVD-assisted counseling. Educational programs will also be beneficial, and cost effectiveness is likely to improve as the number of targeted treatments increases and when the earlier detection of tumors in family members following cascade testing is considered.

A scalable and eco-friendly total synthesis of poly(ADP-ribose) polymerase inhibitor Olaparib

A scalable and eco-friendly total synthesis of PARP inhibitor.