Oza Jay, Doshi Sahil D, Hao Luke, Musi Elgilda, Schwartz Gary K, Ingham Matthew
Division of Hematology and Oncology, Columbia University Irving Medical Center, New York, NY.
Department of Medicine, Columbia University Irving Medical Center, New York, NY.
Semin Oncol. 2020 Dec;47(6):380-389. doi: 10.1053/j.seminoncol.2020.10.002. Epub 2020 Oct 24.
Sarcoma is a rare cancer arising from soft tissue and bone and consists of more than 50 distinct subtypes. There is an increasing emphasis on understanding the cancer biology of individual sarcoma subtypes to inform the development of targeted and immunotherapy-based treatment approaches. While some advances have recently been made in this respect, most sarcomas are still treated with chemotherapy. The homologous recombination DNA repair pathway plays an important role in repairing highly cytotoxic double-stranded DNA breaks and restarting stalled replication forks. A subset of human cancers, notably ovarian, breast, prostate, and pancreatic cancers, harbor defects in components of the homologous recombination repair pathway, such as mutation or loss of BRCA1/2, and are sensitive to treatments which induce double stranded DNA breaks or replication fork arrest, including oral small molecule poly-ADP-ribose polymerase (PARP) inhibitors. Our understanding of DNA repair defects in sarcoma remains at an early stage. Recently, uterine leiomyosarcoma was identified as a sarcoma subtype with characteristic defects in the homologous recombination repair pathway and frequent BRCA2 loss. Preclinical data, presented here, demonstrates marked activity for the PARP inhibitor olaparib in combination with the alkylating agent temozolomide in leiomyosarcoma models. Ongoing research promises to identify other sarcomas with DNA repair defects and may offer a new opportunity for the targeted treatment of this rare, aggressive cancer.
肉瘤是一种起源于软组织和骨骼的罕见癌症，由50多种不同亚型组成。人们越来越重视了解各个肉瘤亚型的癌症生物学特性，以为基于靶向和免疫疗法的治疗方法的开发提供依据。虽然最近在这方面取得了一些进展，但大多数肉瘤仍采用化疗进行治疗。同源重组DNA修复途径在修复高度细胞毒性的双链DNA断裂和重新启动停滞的复制叉方面发挥着重要作用。一部分人类癌症，特别是卵巢癌、乳腺癌、前列腺癌和胰腺癌，在同源重组修复途径的组成部分中存在缺陷，例如BRCA1/2的突变或缺失，并且对诱导双链DNA断裂或复制叉停滞的治疗敏感，包括口服小分子聚ADP - 核糖聚合酶（PARP）抑制剂。我们对肉瘤中DNA修复缺陷的了解仍处于早期阶段。最近，子宫平滑肌肉瘤被确定为一种在同源重组修复途径中具有特征性缺陷且频繁发生BRCA2缺失的肉瘤亚型。本文展示的临床前数据表明，PARP抑制剂奥拉帕利与烷化剂替莫唑胺联合使用在平滑肌肉瘤模型中具有显著活性。正在进行的研究有望识别出其他具有DNA修复缺陷的肉瘤，并可能为这种罕见的侵袭性癌症的靶向治疗提供新机会。
