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聚(ADP-核糖)聚合酶抑制剂:上皮性卵巢癌靶向和个体化治疗的曙光。

Poly (ADP-ribose) polymerase inhibitors: on the horizon of tailored and personalized therapies for epithelial ovarian cancer.

机构信息

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, USA.

出版信息

Curr Opin Oncol. 2012 Sep;24(5):564-71. doi: 10.1097/CCO.0b013e3283564230.


DOI:10.1097/CCO.0b013e3283564230
PMID:22759740
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3799945/
Abstract

PURPOSE OF REVIEW: Management of the epithelial ovarian cancer (EOC) remains a therapeutic challenge, with continued poor overall survival (OS). Given low chemotherapy response rates for recurrent disease and short survival times, new treatment options with improved therapeutic indices for targeting cancer's vulnerability are urgently needed in this patient population. RECENT FINDINGS: In this review, we summarize the recent development and clinical evaluations of inhibitors of poly (ADP-ribose) polymerase (PARP) as novel targeting agents for EOC. PARP inhibitors exploit synthetic lethality to target DNA repair defects in hereditary breast and ovarian cancer.In recent clinical trials, EOC patients with BRCA mutations exhibited favorable responses to the PARP inhibitor olaparib compared with patients without BRCA mutations. Additionally, olaparib has been reported to augment the effects of cisplatin and carboplatin on recurrence-free survival and OS in mice bearing BRCA1/2-deficient tumors.Given that hereditary EOC with deleterious BRCA1/2 mutations and BRCAness sporadic EOC are profoundly susceptible to synthetic lethality with PARP inhibition, it is imperative to identify a population of EOC patients that is likely to respond to PARP inhibitors. Recent studies have identified the gene expression profiles of DNA repair defects and BRCAness that predict clinical outcomes and response to platinum-based chemotherapy in EOC patients. SUMMARY: Ovarian cancer continues to carry the highest mortality among gynecologic cancers in the western world. Clinical development of PARP inhibitors that target DNA repair defects in cancer is a novel and imperative stride in individualized identification of molecular characteristics in management of ovarian cancer.

摘要

目的综述:上皮性卵巢癌(EOC)的治疗仍然是一个挑战,总生存率(OS)持续较差。鉴于复发性疾病的化疗反应率低和生存时间短,对于这类患者群体,迫切需要具有改善治疗指数的靶向癌症脆弱性的新治疗选择。

最近的发现:在这篇综述中,我们总结了聚(ADP-核糖)聚合酶(PARP)抑制剂作为 EOC 新型靶向药物的最新进展和临床评估。PARP 抑制剂利用合成致死性来靶向遗传性乳腺癌和卵巢癌的 DNA 修复缺陷。最近的临床试验表明,与没有 BRCA 突变的患者相比,BRCA 突变的 EOC 患者对 PARP 抑制剂奥拉帕尼有更好的反应。此外,奥拉帕尼已被报道在携带 BRCA1/2 缺陷肿瘤的小鼠中增强顺铂和卡铂对无复发生存和 OS 的作用。鉴于具有有害 BRCA1/2 突变和 BRCA 样的遗传性 EOC 以及 BRCA 样散发性 EOC 对 PARP 抑制的合成致死性非常敏感,因此必须确定可能对 PARP 抑制剂有反应的 EOC 患者人群。最近的研究已经确定了 DNA 修复缺陷和 BRCA 样的基因表达谱,这些预测了 EOC 患者的临床结局和对铂类化疗的反应。

总结:在西方世界,卵巢癌仍然是妇科癌症中死亡率最高的癌症。针对癌症中 DNA 修复缺陷的 PARP 抑制剂的临床开发是在卵巢癌管理中对分子特征进行个体化识别的一项新颖且必要的进展。

相似文献

[1]
Poly (ADP-ribose) polymerase inhibitors: on the horizon of tailored and personalized therapies for epithelial ovarian cancer.

Curr Opin Oncol. 2012-9

[2]
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[3]
Inhibition of poly(ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells.

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[4]
New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors.

Curr Treat Options Oncol. 2016-3

[5]
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Int J Environ Res Public Health. 2022-7-14

[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
Predictive modeling of gene mutations for the survival outcomes of epithelial ovarian cancer patients.

PLoS One. 2024

[2]
Gene expression of non-homologous end-joining pathways in the prognosis of ovarian cancer.

iScience. 2023-9-15

[3]
Transforming Growth Factor Beta and Epithelial to Mesenchymal Transition Alter Homologous Recombination Repair Gene Expression and Sensitize BRCA Wild-Type Ovarian Cancer Cells to Olaparib.

Cancers (Basel). 2023-8-1

[4]
In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer.

Sci Rep. 2021-4-13

[5]
A single nucleotide variant of human PARP1 determines response to PARP inhibitors.

NPJ Precis Oncol. 2020-4-27

[6]
Ovarian cancer: Current status and strategies for improving therapeutic outcomes.

Cancer Med. 2019-9-27

[7]
Combination of triapine, olaparib, and cediranib suppresses progression of BRCA-wild type and PARP inhibitor-resistant epithelial ovarian cancer.

PLoS One. 2018-11-16

[8]
Targeting Cyclin-Dependent Kinases for Treatment of Gynecologic Cancers.

Front Oncol. 2018-8-8

[9]
Androgen receptor inhibitor-induced "BRCAness" and PARP inhibition are synthetically lethal for castration-resistant prostate cancer.

Sci Signal. 2017-5-23

[10]
Opportunities for the repurposing of PARP inhibitors for the therapy of non-oncological diseases.

Br J Pharmacol. 2017-3-26

本文引用的文献

[1]
A DNA repair pathway-focused score for prediction of outcomes in ovarian cancer treated with platinum-based chemotherapy.

J Natl Cancer Inst. 2012-4-13

[2]
Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.

N Engl J Med. 2012-3-27

[3]
Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer.

JAMA. 2012-1-25

[4]
Hereditary ovarian cancer: beyond the usual suspects.

Gynecol Oncol. 2012-2

[5]
Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer.

J Clin Oncol. 2011-12-27

[6]
A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer.

Oncogene. 2011-12-5

[7]
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.

Proc Natl Acad Sci U S A. 2011-10-17

[8]
PARP inhibitors in BRCA gene-mutated ovarian cancer and beyond.

Curr Oncol Rep. 2011-12

[9]
Reduced level of ribonucleotide reductase R2 subunits increases dependence on homologous recombination repair of cisplatin-induced DNA damage.

Mol Pharmacol. 2011-8-29

[10]
Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.

Lancet Oncol. 2011-8-19

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