Xie Tao, Dickson Kristie-Ann, Yee Christine, Ma Yue, Ford Caroline E, Bowden Nikola A, Marsh Deborah J
Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia.
School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia.
Cancers (Basel). 2022 Sep 23;14(19):4621. doi: 10.3390/cancers14194621.
The advent of molecular targeted therapies has made a significant impact on survival of women with ovarian cancer who have defects in homologous recombination repair (HRR). High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, with over 50% displaying defective HRR. Poly ADP ribose polymerases (PARPs) are a family of enzymes that catalyse the transfer of ADP-ribose to target proteins, functioning in fundamental cellular processes including transcription, chromatin remodelling and DNA repair. In cells with deficient HRR, PARP inhibitors (PARPis) cause synthetic lethality leading to cell death. Despite the major advances that PARPis have heralded for women with ovarian cancer, questions and challenges remain, including: can the benefits of PARPis be brought to a wider range of women with ovarian cancer; can other drugs in clinical use function in a similar way or with greater efficacy than currently clinically approved PARPis; what can we learn from long-term responders to PARPis; can PARPis sensitise ovarian cancer cells to immunotherapy; and can synthetic lethal strategies be employed more broadly to develop new therapies for women with ovarian cancer. We examine these, and other, questions with focus on improving outcomes for women with ovarian cancer.
分子靶向治疗的出现对同源重组修复(HRR)存在缺陷的卵巢癌女性患者的生存率产生了重大影响。高级别浆液性卵巢癌(HGSOC)是卵巢癌最常见的组织学亚型,超过50%的病例显示HRR存在缺陷。聚ADP核糖聚合酶(PARP)是一类催化ADP核糖转移至靶蛋白的酶,在包括转录、染色质重塑和DNA修复等基本细胞过程中发挥作用。在HRR缺陷的细胞中,PARP抑制剂(PARPi)会导致合成致死从而引发细胞死亡。尽管PARPi为卵巢癌女性患者带来了重大进展,但问题和挑战依然存在,包括:PARPi的益处能否惠及更广泛的卵巢癌女性患者;临床使用的其他药物是否能以类似方式发挥作用或比目前临床批准的PARPi具有更高疗效;我们能从PARPi的长期反应者身上学到什么;PARPi能否使卵巢癌细胞对免疫疗法敏感;以及合成致死策略能否更广泛地用于开发针对卵巢癌女性患者的新疗法。我们围绕改善卵巢癌女性患者的治疗结果审视这些及其他问题。