HiberCell, Inc., New York City, New York.
Curia, Buffalo, New York.
Clin Cancer Res. 2023 Dec 1;29(23):4870-4882. doi: 10.1158/1078-0432.CCR-23-1182.
Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI).
HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC.
VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group.
By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.
肿瘤在缺氧和营养缺乏时激活蛋白激酶 R（PKR）样内质网激酶（PERK，也称为 EIF2AK3），作为一种减轻应激的策略。在这里，我们测试了这样一个假设，即通过抑制 PERK 来增强标准护理血管内皮生长因子受体酪氨酸激酶抑制剂（VEGFR-TKI）的抗肿瘤功效。
HC-5404 被鉴定为一种有效的选择性 PERK 抑制剂，具有良好的体内特性。然后，在体内对多个肾细胞癌（RCC）肿瘤模型同时进行 HC-5404 和 VEGFR-TKI 治疗，随时间测量肿瘤体积，并通过蛋白分析和免疫组化评估肿瘤反应。
VEGFR-TKI（包括阿昔替尼、卡博替尼、仑伐替尼和舒尼替尼）在 786-O RCC 异种移植瘤中诱导 PERK 激活。与 HC-5404 联合治疗可抑制肿瘤中的 PERK，并显著增强多种 RCC 模型中 VEGFR-TKI 的抗肿瘤作用，导致肿瘤停滞或消退。对肿瘤切片的分析表明，HC-5404 通过抑制新血管和成熟肿瘤血管，增强了阿昔替尼和仑伐替尼的抗血管生成作用。阿昔替尼单药治疗进展的异种移植瘤仍然对联合治疗敏感，联合组中约有 20%的肿瘤消退。在对 18 个 RCC 患者来源异种移植瘤（PDX）模型的测试中，联合治疗相对于单药治疗诱导了更大的抗肿瘤作用。在这项单动物研究中，联合组中有 9 个模型的肿瘤相对于基线消退了≥50%。
通过破坏 VEGFR-TKI 引发的适应性应激反应，HC-5404 为改善 RCC 中既定标准护理疗法的抗肿瘤效果提供了临床机会。
