New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors.
New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors.
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DOI：
10.1007/s11864-015-0378-9
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发表时间：
2016-03
影响因子：
4.3
通讯作者：
Tewari KS
中科院分区：
文献类型：
--
作者：
Liu FW;Tewari KS
意见陈述聚（ADP-核糖）聚合酶（PARP）抑制剂已成为一类新的抗癌药物，特别是用于同源重组途径异常的恶性肿瘤，如BRCA 1和BRCA 2基因突变的肿瘤。奥拉帕尼是一种有效的PARP 1和PARP 2抑制剂，已被证明可显著增加与生殖系BRCA突变相关的复发性卵巢癌女性的无进展生存期（PFS），目前已被批准用于这些患者的四线治疗。PARP抑制剂（PARPi）靶向被称为合成致死性的遗传现象，以利用错误的DNA修复机制。虽然卵巢癌富含具有已知同源重组缺陷的肿瘤群体，但正在进行研究以帮助确定其他妇科癌症中可能通过合成致死机制表现出对PARPi易感性的途径。ARIEL 2试验前瞻性地确定了识别HRD患者的预测性试验。癌症治疗的未来可能会结合这些HRD测定来确定患者的最佳治疗计划。虽然PARPi在非卵巢妇科癌症中的作用不太清楚，但HRD预测性测定的发现可能为这些富含HRD患者的其他妇科癌症的临床试验打开大门。识别肿瘤缺乏同源修复或具有HRD样行为的患者将癌症治疗推向个体化治疗，以最大限度地提高妇科癌症患者的治疗效果和生活质量。
Opinion statementInhibitors of poly (ADP-ribose) polymerase (PARP) have emerged as a new class of anti-cancer drugs, specifically for malignancies bearing aberrations of the homologous recombination pathway, like those with mutations in the BRCA 1 and BRCA 2 genes. Olaparib, a potent PARP1 and PARP2 inhibitor, has been shown to significantly increase progression-free survival (PFS) in women with recurrent ovarian cancer related to a germline BRCA mutation and is currently approved fourth-line treatment in these patients. PARP inhibitors (PARPi) target the genetic phenomenon known as synthetic lethality to exploit faulty DNA repair mechanisms. While ovarian cancer is enriched with a population of tumors with known homologous recombination defects, investigations are underway to help identify pathways in other gynecologic cancers that may demonstrate susceptibility to PARPi through synthetically lethal mechanisms. The ARIEL2 trial prospectively determined a predictive assay to identify patients with HRD. The future of cancer therapeutics will likely incorporate these HRD assays to determine the best treatment plan for patients. While the role of PARPi is less clear in non-ovarian gynecologic cancers, the discovery of a predictive assay for HRD may open the door for clinical trials in these other gynecologic cancers enriched with patients with HRD. Identification of patients with tumors deficient in homologous repair or have HRD-like behavior moves cancer treatment towards individualized therapies in order to maximize treatment effect and quality of life for women living with gynecologic cancers.
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影响因子：
28.2
作者：
Birkbak NJ;Wang ZC;Kim JY;Eklund AC;Li Q;Tian R;Bowman-Colin C;Li Y;Greene-Colozzi A;Iglehart JD;Tung N;Ryan PD;Garber JE;Silver DP;Szallasi Z;Richardson AL
通讯作者：
Richardson AL
影响因子：
45.3
作者：
Fong, Peter C.;Yap, Timothy A.;Kaye, Stan B.
通讯作者：
Kaye, Stan B.
影响因子：
8.8
作者：
Del Conte, G.;Sessa, C.;von Moos, R.;Vigano, L.;Digena, T.;Locatelli, A.;Gallerani, E.;Fasolo, A.;Tessari, A.;Cathomas, R.;Gianni, L.
通讯作者：
Gianni, L.
影响因子：
158.5
作者：
Burger, Robert A.;Brady, Mark F.;Liang, Sharon X.
通讯作者：
Liang, Sharon X.
影响因子：
11.5
作者：
Evers, Bastiaan;Drost, Rinske;Jonkers, Jos
通讯作者：
Jonkers, Jos