HIF2 Inactivation and Tumor Suppression with a Tumor-Directed RNA-Silencing Drug in Mice and Humans.
HIF2 Inactivation and Tumor Suppression with a Tumor-Directed RNA-Silencing Drug in Mice and Humans.
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DOI：
10.1158/1078-0432.ccr-22-0963
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发表时间：
2022-12-15
影响因子：
11.5
通讯作者：
Brugarolas, James
中科院分区：
文献类型：
--
作者：
Ma, Yuanqing;Joyce, Allison;Brandenburg, Olivia;Saatchi, Faeze;Stevens, Christina;Tcheuyap, Vanina Toffessi;Christie, Alana;Do, Quyen N.;Fatunde, Oluwatomilade;Macchiaroli, Alyssa;Wong, So C.;Woolford, Layton;Yousuf, Qurratulain;Miyata, Jeffrey;Carrillo, Deyssy;Onabolu, Oreoluwa;McKenzie, Tiffani;Mishra, Akhilesh;Hardy, Tanner;He, Wei;Li, Daniel;Ivanishev, Alexander;Zhang, Qing;Pedrosa, Ivan;Kapur, Payal;Schluep, Thomas;Kanner, Steven B.;Hamilton, James;Brugarolas, James
HIF2α是肾癌的关键驱动因素。我们先前在肿瘤移植(TGS)研究中发现，大约50%的肾透明细胞癌(CCRCC)依赖于HIF2α。然而，长期治疗会导致耐药性突变，我们也在人类中发现了这种突变。在这里，我们评估了一种肿瘤导向的、系统递送的小干扰RNA药物(SiHIF2siHIF2)，该药物对野生型和耐药突变的hif2α具有活性。使用我们认证的TG平台，我们进行了药代动力学和药效学分析，评估摄取、HIF2α沉默、靶基因失活和抗肿瘤活性。对siHIF2和PT2399进行了正交性RNA-seq研究以确定HIF2转录组。分析扩展到从siHIF2 I期临床试验(NCT04169711)参与者和相应患者的研究活检中产生的TG线，该患者是一名接受广泛治疗的患者，患有快速进展的ccRCC和副肿瘤性红细胞增多症，可能证明对HIF2的依赖。SiHIF2被CcRCC TGS摄取，有效地耗尽HIF2α，去激活正交性定义的效应通路(包括Myc和新的E2F通路)，下调细胞周期基因，抑制肿瘤生长。对研究对象TG的影响与患者相似，在肿瘤活检中HIF2α被沉默，循环促红细胞生成素下调，红细胞增多症被抑制，并诱导部分反应。据我们所知，这是第一个用系统性的、针对肿瘤的、RNA沉默的药物来功能灭活癌蛋白和抑制肿瘤的例子。这些研究为肿瘤靶向药物抑制HIF2RNA在肾细胞癌中的作用提供了原理证明，并为肿瘤导向的α治疗建立了范例。
HIF2α is a key driver of kidney cancer. Using a belzutifan analogue (PT2399), we previously showed in tumorgrafts (TGs) that ~50% of clear cell renal cell carcinomas (ccRCCs) are HIF2α dependent. However, prolonged treatment induced resistance mutations, which we also identified in humans. Here, we evaluated a tumor-directed, systemically-delivered, siRNA drug (siHIF2) active against wild-type and resistant mutant HIF2α. Using our credentialed TG platform, we performed pharmacokinetic and pharmacodynamic analyses evaluating uptake, HIF2α silencing, target gene inactivation and anti-tumor activity. Orthogonal RNA-seq studies of siHIF2 and PT2399 were pursued to define the HIF2 transcriptome. Analyses were extended to a TG line generated from a study biopsy of a siHIF2 phase I clinical trial (NCT04169711) participant and the corresponding patient, an extensively pretreated individual with rapidly progressive ccRCC and paraneoplastic polycythemia likely evidencing a HIF2 dependency. siHIF2 was taken up by ccRCC TGs, effectively depleted HIF2α, deactivated orthogonally-defined effector pathways (including Myc and novel E2F pathways), downregulated cell cycle genes and inhibited tumor growth. Effects on the study subject TG mimicked those in the patient, where HIF2α was silenced in tumor biopsies, circulating erythropoietin was downregulated, polycythemia was suppressed, and a partial response was induced. To our knowledge, this is the first example of functional inactivation of an oncoprotein and tumor suppression with a systemic, tumor-directed, RNA-silencing drug. These studies provide a proof-of-principle of HIF2α inhibition by RNA-targeting drugs in ccRCC and establish a paradigm for tumor-directed RNA-based therapeutics in cancer.
DOI：
10.4161/trns.23680
发表时间：
2013-03
期刊：
Transcription
影响因子：
--
作者：
Bakker WJ;Weijts BG;Westendorp B;de Bruin A
通讯作者：
de Bruin A
PBK 在泛癌症队列中的预后、调节和免疫相关作用的组学和药物基因组学证据
影响因子：
5
作者：
Liu Y;Xiang J;Peng G;Shen C
通讯作者：
Shen C