Murthy Pooja, Muggia Franco
Department of Medicine, Maimonides Cancer Center, Brooklyn, NY 11220, USA.
New York University School of Medicine, New York, NY 10016, USA.
Cancer Drug Resist. 2019 Sep 19;2(3):665-679. doi: 10.20517/cdr.2019.002. eCollection 2019.
Following years in development, poly-adenosyl-ribose polymerase (PARP) inhibitors continue to advance the treatment of ovarian and breast cancers, particularly in patients with pathogenic mutations. Differences in clinical trial design have contributed to distinct indications for each of the PARP inhibitors. Toxicity patterns are also emerging that suggest agents differ in their normal tissue tolerance - beyond what might be expected by dose variations and/or exposure to prior treatment. PARP inhibitor resistance is an increasingly relevant issue as the drugs move to the forefront of advanced ovarian/breast cancer treatment, and is an active area of ongoing research. This review examines the PARP inhibitor clinical trials that have led to approved indications in ovarian and breast cancers, PARP inhibitor targets and pharmacological differences between the PARP inhibitors, emerging mechanisms of resistance, and key clinical questions for future development.
经过多年的研发，聚腺苷酸核糖聚合酶（PARP）抑制剂在卵巢癌和乳腺癌的治疗方面不断取得进展，尤其是在患有致病性突变的患者中。临床试验设计的差异导致了每种PARP抑制剂具有不同的适应症。毒性模式也逐渐显现，表明这些药物在正常组织耐受性方面存在差异——超出了剂量变化和/或既往治疗暴露可能预期的范围。随着这些药物成为晚期卵巢癌/乳腺癌治疗的前沿药物，PARP抑制剂耐药性问题日益突出，并且是正在进行的研究的一个活跃领域。本综述探讨了已导致卵巢癌和乳腺癌获批适应症的PARP抑制剂临床试验、PARP抑制剂的靶点以及它们之间的药理学差异、新出现的耐药机制以及未来发展的关键临床问题。
