Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
Gillette Center for Gynecologic Oncology, Massachusetts General Hospital, Boston, Massachusetts.
Clin Cancer Res. 2015 Feb 15;21(4):808-18. doi: 10.1158/1078-0432.CCR-14-2810. Epub 2014 Dec 18.
Increased tumor hypoxia and hence elevated hypoxia-inducible factor-1α (HIF1α) is thought to limit the efficacy of vascular endothelial growth factor (VEGF) pathway-targeting drugs by upregulating adaptive resistance genes. One strategy to counteract this is to combine antiangiogenic drugs with agents able to suppress HIF1α. One such possibility is the investigational drug CRLX101, a nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a known topoisomerase-I poison.
CRLX101 was evaluated both as a monotherapy and combination with bevacizumab in a preclinical mouse model of advanced metastatic ovarian cancer. These preclinical studies contributed to the rationale for undertaking a phase II clinical study to evaluate CRLX101 monotherapy in patients with advanced platinum-resistant ovarian cancer.
Preclinically, CRLX101 is highly efficacious as a monotherapy when administered at maximum-tolerated doses. Furthermore, chronic low-dose CRLX101 with bevacizumab reduced bevacizumab-induced HIF1α upregulation and resulted in synergistic efficacy, with minimal toxicity in mice. In parallel, initial data reported here from an ongoing phase II clinical study of CRLX101 monotherapy shows measurable tumor reductions in 74% of patients and a 16% RECIST response rate to date.
Given these preclinical and initial clinical results, further clinical studies are currently evaluating CRLX101 in combination with bevacizumab in ovarian cancer and warrant the evaluation of this therapy combination in other cancer types where HIF1α is implicated in pathogenesis, as it may potentially be able to improve the efficacy of antiangiogenic drugs.
人们认为，肿瘤缺氧增加，从而导致缺氧诱导因子-1α（HIF1α）升高，通过上调适应性耐药基因，限制了血管内皮生长因子（VEGF）通路靶向药物的疗效。对抗这种情况的一种策略是将抗血管生成药物与能够抑制 HIF1α 的药物联合使用。一种可能性是研究药物 CRLX101，它是一种含有喜树碱有效载荷的纳米颗粒药物偶联物（NDC），喜树碱是一种已知的拓扑异构酶 I 抑制剂。
CRLX101 作为单一疗法以及与贝伐单抗联合在晚期转移性卵巢癌的临床前小鼠模型中进行了评估。这些临床前研究为进行评估 CRLX101 单药治疗晚期铂耐药卵巢癌患者的 II 期临床研究提供了依据。
临床前研究表明，CRLX101 作为单一疗法在最大耐受剂量下具有高度疗效。此外，贝伐单抗联合慢性低剂量 CRLX101 可降低贝伐单抗诱导的 HIF1α 上调，并产生协同疗效，在小鼠中毒性最小。与此并行，此处报告的正在进行的 CRLX101 单药治疗的 II 期临床研究的初步数据显示，74%的患者有可测量的肿瘤缩小，到目前为止，RECIST 反应率为 16%。
鉴于这些临床前和初步临床结果，目前正在对卵巢癌中 CRLX101 与贝伐单抗联合进行进一步的临床研究，并需要评估这种治疗联合在其他涉及 HIF1α 在发病机制中的癌症类型中的应用，因为它可能有潜力提高抗血管生成药物的疗效。
