Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD 21287, USA.
Cancer J. 2013 Jan-Feb;19(1):99-106. doi: 10.1097/PPO.0b013e31827e0b86.
It was first posited in the 1970s that angiogenesis may prove to be a useful target for anticancer therapies. Since then, a number of agents have been developed and tested across a range of tumor types; however, to date, there have unfortunately been more failures than successes. Prostate cancer (PCa) is no exception in this regard, and despite a strong preclinical rationale for targeting angiogenesis in men with PCa, there has yet to be an antiangiogenic therapy proven to prolong survival in this group of patients. Drugs have been developed to target a host of angiogenesis mediators. These include vascular endothelial growth factor (VEGF), the VEGF receptors, antiangiogenic factors (e.g., thrombospondin-1), and downstream mediators of angiogenesis (e.g., hypoxia-inducible factor-1α and MET). At present, there are 2 drugs being tested in the phase III setting for men with PCa: cabozantinib and tasquinimod. Cabozantinib, a dual VEGF receptor-2/MET inhibitor, has shown dramatic beneficial effects on radiographically evident bone metastases and pain in the phase II setting. There are currently 2 large phase III trials underway to further investigate cabozantinib's role in treating men with PCa. Both trials randomize subjects to cabozantinib versus mitoxantrone: one is designed to evaluate overall survival, and the other, pain response durability. The other drug, tasquinimod, has a somewhat poorly understood mechanism of action. It is thought to exert an antiangiogenic effect through the inhibition of myeloid-derived suppressor cells, key to the support of an angiogenic environment, and down-regulation of hypoxia-inducible factor-1α. A phase II trial randomizing men to tasquinimod versus placebo revealed a median progression-free survival advantage in the experimental arm (7.6 vs. 3.3 months with placebo; P = 0.0042). Based on these encouraging phase II results, a randomized, double-blind, placebo-controlled trial in men with metastatic castration-resistant PCa was launched. That trial is powered for a primary endpoint of progression-free survival and is expected to enroll 1200 men.
早在 20 世纪 70 年代，就有人提出血管生成可能成为癌症治疗的一个有用靶点。从那时起，已经开发并测试了许多针对各种肿瘤类型的药物；然而，到目前为止，失败的例子比成功的例子更多。前列腺癌（PCa）在这方面也不例外，尽管针对 PCa 男性的血管生成靶向治疗具有强有力的临床前理论依据，但到目前为止，还没有一种抗血管生成疗法被证明能延长这组患者的生存时间。已经开发了针对一系列血管生成介质的药物。这些药物包括血管内皮生长因子（VEGF）、VEGF 受体、抗血管生成因子（如血小板反应蛋白-1）和血管生成的下游介质（如缺氧诱导因子-1α和 MET）。目前，有 2 种药物正在进行 III 期临床试验，用于治疗 PCa 男性：卡博替尼和塔昔单抗。卡博替尼是一种双重 VEGF 受体-2/MET 抑制剂，在 II 期临床试验中，对影像学明显的骨转移和疼痛有显著的有益作用。目前有 2 项大型 III 期试验正在进行，以进一步研究卡博替尼在治疗 PCa 男性中的作用。这两项试验都将受试者随机分为卡博替尼组和米托蒽醌组：一项旨在评估总生存期，另一项旨在评估疼痛反应的持久性。另一种药物塔昔单抗的作用机制尚不完全清楚。它被认为通过抑制髓样来源的抑制细胞发挥抗血管生成作用，髓样来源的抑制细胞是支持血管生成环境的关键，同时下调缺氧诱导因子-1α。一项将男性随机分为塔昔单抗组和安慰剂组的 II 期试验显示，实验组的中位无进展生存期有优势（实验组为 7.6 个月，安慰剂组为 3.3 个月；P = 0.0042）。基于这些令人鼓舞的 II 期结果，一项针对转移性去势抵抗性 PCa 男性的随机、双盲、安慰剂对照试验启动。该试验的主要终点是无进展生存期，预计将纳入 1200 名男性。
