Efficacy and safety of olaparib in adjuvant therapy of BRCA1/2 mutated HER2-negative breast cancer：a meta-analysis / 中国药房

OBJECTIVE To systematically evaluate the efficacy and safety of olaparib in adjuvant therapy of breast cancer susceptibility gene （BRCA） 1/2 mutated human epidermal growth factor receptor 2 （HER2）-negative breast cancer， and to provide evidence-based reference for clinical treatment. METHODS Retrieved from CNKI， VIP， Wanfang data， PubMed， ScienceDirect， the Cochrane Library and Embase databases， randomized controlled trials about adjuvant therapy of olaparib （trial group） versus adjuvant therapy of other drugs （control group） were collected. After literature screening and data extraction， meta-analysis， publication bias analysis and sensitivity analysis were performed by using RevMan5.4 software. RESULTS A total of 5 randomized controlled trials were included， with a total of 2 633 patients， including 1 495 cases in trial group and 1 174 cases in control group. Meta-analysis showed that in terms of efficacy， compared with control group， overall survival [HR＝1.02， 95%CI （1.01，1.03）， P＝0.000 8] and progression-free survival [HR＝1.78， 95%CI（1.46，2.17）， P＜0.000 01] were longer significantly in the trial group. In terms of safety， compared with the control group， the incidence of adverse drug reactions at any level in the trial group was higher [RR＝1.41， 95%CI （1.12， 1.78）， P＝0.004]， while there was no statistically significant difference in the incidence of adverse drug reactions above level 3 between the two groups [RR＝1.75， 95%CI （0.82， 3.74）， P＝0.15]. The results of publication bias indicated that the possibility of publication bias in this study was relatively low. The results of sensitivity analysis showed that the results obtained in this study were robust. CONCLUSIONS Compared with patients without adjuvant therapy of olaparib， adjuvant therapy of olaparib can prolong overall survival and progression-free survival of patients with BRCA1/2 mutated HER2-negative breast cancer，but the risk of adverse drug reactions is relatively high.

Management of human epidermal growth factor receptor 2杗egative metastatic breast cancer: Role of poly adenosine diphosphate (ADP?ribose) polymerase inhibitors

Human epidermal growth factor receptor 2 (HER2)?negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor (HR)?positive and HR?negative breast cancer (or TNBC), which have different therapies and treatment challenges. Though endocrine therapy (ET) remains the treatment backbone in HR?positive HER2?negative cases, about 40% of the patients show intrinsic or acquired resistance to ET due to multiple mechanisms. Combining different therapies such as ET and other targeted therapies with or without chemotherapy fails to give continued benefit, unlike cyclin?dependent kinase (CDK) 4/6 inhibitors that have shown a great benefit. TNBC has conventionally been treated ineffectively with systemic chemotherapy. Recently, poly (ADP?ribose) polymerase inhibitors (PARPi) have emerged for HER2?negative breast cancer (BC) patients, including TNBC. Olaparib and talazoparib have recently been approved in germline BRCA?mutated (gBRCAm) HER2?negative MBC. Additionally, ongoing trials of PARPi in combination with various therapies are expected to provide more and better treatment options for gBRCAm HER2?negative breast cancer.

A review on mechanisms of resistance to PARP inhibitors

Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP?ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA?associated cancers, especially high?grade OC and breast cancers. They lead to synthetic lethality in BRCA?mutated cells by stalling the replication forks in homologous recombination?deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA?associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance

Optimization and screening of carrier for solid dispersion of olaparib based on the solubility parameter and differential scanning calorimetry / 药学学报

Solid dispersion, a dispersion system in which drug molecules are highly dispersed in carrier materials, has been commonly used to improve the solubility and dissolution rate of poorly soluble drugs. The miscibility between drug and carrier is crucial to improve the dissolution performance and stability of solid dispersion. Therefore, the selection of carrier types and the optimization of drug loading are very important. In the current study, the solubility parameter method and Flory-Huggins theory were used to predict the miscibility between olaparib (OLP) and different carriers (VA64, Soluplus, Plasdone S630 and Kollidon K29/32). Besides, the carrier material with good miscibility was experimentally screened by differential scanning calorimetry (DSC). The optimum of drug-carrier ratio was further performed based on the miscibility phase diagram of drug and carrier. Theoretical calculation and experimental evaluation showed that the miscibility of OLP and VA64 was the best, and the drug loading of 30% could meet the requirements of large drug loading and physical stability. Polarizing light microscope, X-ray powder diffraction, DSC and laser confocal Raman spectroscopy exhibited that OLP was amorphous form in the solid dispersion system. Powder dissolution test demonstrated that the solid dispersion showed significantly enhanced dissolution rate in comparison to crystalline OLP. In this study, theoretical calculation and experimental evaluation were used to screen the types of carriers and optimize the drug loading, which provides an efficient strategy for the selection of carrier and the amount used in solid dispersion.

PROfound: A new hope for precise treatment of prostate cancer / 中国临床药理学与治疗学

Metastatic castrate-resistant prostate cancer (mCRPC) is the last stage of prostate cancer. Although new hormonal agents and taxane-based chemotherapies occurred for mCRPC treatment, the overall survival of mCRPC patients is limited. Olaparib is an inhibitor of poly ADP-ribose polymerase (PARP), which has a key role in DNA damage response. It has been approved for ovarian cancer and breast cancer treatment. PROfound, a phase III clinical trial of olaparib in mCRPC treatment, has been reported in 2019 ESMO and 2020 ASCO-GU. In this paper, we will bring the results and updates of PROfound.

Olaparib induced senescence under P16 or P53 dependent manner in ovarian cancer / 부인종양

OBJECTIVE: Poly (ADP-ribose) polymerase (PARP) is an important molecule in the early stress response of DNA damage, which is involved in DNA damage repair and cellular senescence. Olaparib, as PARP inhibitor, has an anti-tumor effect on high grade serous ovarian cancer, but its effects on cellular senescence have not been reported. This study intends to explore the role of olaparib in the regulation of senescence in ovarian cancer cells. METHODS: The effects of olaparib on the senescence of ovarian cancer cells were detected by using the senescence-associated β-galactosidase (SA-β-Gal) and senescence-associated heterochromatin aggregation (SAHF). Quantitative real-time polymerase chain reaction was used to analyze the senescence-associated secretory phenotype (SASP). Cell cycle and apoptosis were detected by flow cytometry. The effect of olaparib on tumor growth was analyzed in a nude mouse xenograft transplantation model. RESULTS: Long-term (6 days) treatment with olaparib (5 μM) significantly inhibited the growth of ovarian cancer cells, leading to arrest the cell cycle at G0/G1 phase, significant increase the number of positive SA-β-Gal stained cells and positive SAHF cells. The expression of P16 and retinoblastoma protein (p-RB) were significantly enhanced in SKOV3 cells under olaparib treated, meanwhile, the expression of P53 and p-RB were upregulated in A2780 cells. In OVCAR-3 cells, the expression of P53 was downregulated and p-RB was upregulated. Mice with SKOV3 xenograft transplantation was given olaparib (10 mg/kg/day) via abdominal cavity administration, the tumor volume was reduced (p < 0.01). CONCLUSION: Continuous low dosage administration of olaparib induced senescence under P16 or P53 dependent manner in ovarian cancer.

Olaparib regulates inflammatory response in lipopolysaccharide-induced A549 cells through PARP-1 pathway / 中国药理学与毒理学杂志

OBJECTIVE To investigate the protective effect of olaparib on the inflammatory damage to alveolar epithelial cells induced by lipopolysaccharide (LPS). METHODS The alveolar epithelial cells (A549) were cultured in vitro and incubated with LPS 10 mg-L-1 and olaparib 10 and 25 μmol-L-1 for 24 h. The levels of cytokines interleukin 6 (IL-6), IL-8, and IL-10 were detected by enzyme linked immunosorbent assay (ELISA), the mRNA expression levels of TNF-α, IL-1β, IL-6, IL-8, and ICAM-1 were analyzed by real-time PCR, the level of ROS was analyzed by flow cytometry, and the expression of poly (ADP-ribose) polymerase-1 (PARP-1) and phosphorylation of proteins involved in NF-ΚB signaling pathway in cells were detected by Western blotting. RESULTS Compared with LPS 10 mg-L-1 injury group, olaparib 10 and 25 μmol·L-1 could significantly reduce the release of IL-6, IL-8 and ROS levels in A549 cells induced by LPS (P<0.01), and increase the release of IL-10 (P<0.01). Olaparib 10 and 25 μmol·L-1 could also inhibit the mRNA expressions of TNF-α, IL-1β, IL-6, IL-8, and ICAM-1 (P<0.01), and inhibit the expression of PARP-1 and phosphorylation proteins involved in NF-ΚB signaling pathway induced by LPS (P<0.01). CONCLUSION Olaparib has some protective effect on inflammatory damage and oxidative stress in alveolar epithelial cells induced by LPS, and the mechanism may be that it inhibits the expression and release of cytokines by down-regulating the expression of PARP-1 and subsequently affecting the activation of the NF-ΚB pathway.

Effect of Olaparib on Ovarian Cancer SKOV3 Cell Line Proliferation by Inhibiting the PI3K/AKT/mTOR Signaling Pathway / 中国药学杂志

OBJECTIVE: To analyze the involvement of PI3K/AKT/mTOR signaling pathway on the inhibiting the proliferation of ovarian cancer SKOV3 cell line by olaparib. METHODS: The SKOV3 cells were randomly divided into five groups: control group, olaparib low dose group (10 mg•L-1), olaparib medium dose group (30 mg•L-1), olaparib high dose group (90 mg•L-1), and PI3K protein inhibitor LY294002 group (10 mg•L-1). In addition to the control group, the rest of the cells were incubated with the corresponding doses of the compounds. DAPI and Western blotting were used to analyze the expression of apoptotic protein. qPCR, Western blotting and immunocytochemistry were adopted to detect the expression of PI3K/AKT/mTOR signaling pathway related proteins. RESULTS: After olaparib treatment, the proliferation of ovarian cancer SKOV3 cells was significantly inhibited (P<0.05). Apoptotic bodies in SKOV3 cells increased gradually, and the expression of caspase 3 and caspase 9 increased gradually (P<0.05), PI3K, AKT and mTOR expression gradually decreased (P<0.05) after olaparib medication. With the increase of olaparib level, the above effects were more obvious (P<0.05). CONCLUSION: Olaparib has an inhibitory effect on ovarian cancer SKOV3 cells, and it may play a role by inhibiting the PI3K/AKT/mTOR signaling pathway.

Inhibitory effect of PARP inhibitor olaparib on acute myeloid leukemia HL-60 cells / 实用肿瘤学杂志

Objective The inhibitory effect of the PARP inhibitor olaparib on human acute myeloid leukemia HL-60 cells was studied. Methods The HL-60 cells in logarithmic growth phase were treated with different concentrations(1. 25,2. 5,5 and 10 μmol/L) of olaparib for different time. The CCK-8 assay was used to detect the inhibitory effect of olaparib on HL-60 cells. The apoptotic level of HL-60 cells was detected by Annexin-V/PI double staining method,and the expression of related signal proteins ( PARP-1 and caspase-3)in HL-60 cells was detected by Western blot. Results HL-60 cells were inhibited by olaparib at dif-ferent concentrations(1. 25,2. 5,5 and 10 μmol/L) for 48 h,and the inhibition rate gradually increased with the prolongation of the action time;at the same time,the apoptotic rate was increased in HL-60 cells after olaparib treatment for 48 h,showing a dose-de-pendent manner;the PARP activity was inhibited and caspase-3 was activated in HL-60 cells treated with olaparib. Conclusion The PARP inhibitor olaparib not only inhibits proliferation of HL-60 cells,but it also promotes apoptosis of HL-60 cells by inhibi-ting PARP activity and activating caspase-3.

Effect of Olaparib on proliferation activity and radiosensitization of human non-small cell lung cancer cells / 国际生物医学工程杂志

Objective To investigate the effects of Olaparib on cell proliferation and radiosensitization of human non-small cell lung cancer cells.Methods Non-small cell lung H460 and H1299 cell lines were cultured in vitro and the cells in logarithmic growth phase were selected for experiments.MTT and colony formation assays were used to determine cell proliferation and radiosensitization,respectively.Single cell gel electrophoresis assay (comet assay) was used to detect irradiation-induced DNA damage.Results The results of MTT assay showed that Olaparib inhibited the proliferation of H460 and H1299 cells in a dose-dependent pattern (all P＜0.05).H1299 cell line was more sensitive to Olaparib than H460 cells.The results of colony formation assay showed that Olaparib enhanced the radiosensitizition of H460 and H1299 cells (all P＜0.05).The results of comet assay showed that Olaparib increased γ ray-induced DNA damage.Conclusions Olapani can enhance the radiosensitization of human non-small cell lung cancer cells,and the radiosensitization effect of Olaparib may be associated with the inhibition of cell proliferation and induction of irradiation-induced DNA damage.