Improving radiolabeled imaging and targeting of HER2 positive EG cancers using lovastatin

项目摘要/摘要 食管胃(EG)癌的发病率正在迅速增加，特别是在年轻男性中。在临床患者中 分类为HER2阳性(ERBB2扩增和/或2+/3+蛋白过度表达)， 治疗性抗HER2抗体曲妥珠单抗和标准细胞毒治疗延长无进展和全面 生死存亡。然而，固有的肿瘤耐药性或在治疗过程中形成的耐药性机制限制了 32%的患者临床受益，其他抗HER2治疗性抗体在治疗EG的临床试验中失败 癌症。因此，需要补充生物标记物和方法来治疗此类患者。由临床前指导 数据表明，小窝蛋白-1(CAV1)--富含胆固醇的质膜内陷的主要蛋白质 -减少曲妥珠单抗与HER2阳性EG肿瘤的结合，我们启动了回顾性临床分析以验证 CAV1作为HER2的互补生物标志物。值得注意的是，卡普兰-迈耶生存分析表明 表达高CAV1(IHC 2+/3+)的HER2+EG肿瘤的总体存活率低于低表达CAV1的肿瘤 曲妥珠单抗治疗后(IHC 0/+1)。这些有希望的初步结果促使我们在药理学上 用降胆固醇药物洛伐他汀耗尽CAV1(存在于胆固醇膜区域)。 在这里，我们将对HER2阳性的EG肿瘤患者进行回顾性分析，以评估HER2的表达 异质性、ERBB2扩增、CAV1染色和遗传改变的存在(拷贝数 变异)与曲妥珠单抗耐药有关。我们将分析医疗记录以确定是否并发 他汀类药物的使用与曲妥珠单抗的增强反应有关。除了回顾分析外，我们还将 使用患者来源的EG异种移植(PDX)进行随机成像和治疗性临床前研究 代表HER2+/CAV1高和HER2+/CAV1低肿瘤群体。我们将确定分子成像 (1)对照生理盐水、(2)曲妥珠单抗治疗的PDX患者的~(89)Zr-曲妥珠单抗显像及疗效 单独，(3)洛伐他汀，或(4)曲妥珠单抗与洛伐他汀的组合，以确定 赋予药物敏感性和对这种有希望的研究组合的耐药性。AIM 1将验证CAV1作为 HER2，AIM 2的补充生物标记物将确定他汀类药物对临床的潜在剂量学影响 成像并识别受益于曲妥珠单抗/洛伐他汀组合的EG肿瘤群体，Aim 3将 验证他汀类药物作为HER2靶向显像和全身放射性核素的新药理学方法的使用 能够减少靶外辐射剂量的治疗(内放射治疗)。所有这三个目标都将产生重要的 关于使用他汀类药物改善曲妥珠单抗疗效的新的临床前数据，这应该会提供一个极好的 为未来的许多研究奠定基础，包括曲妥珠单抗/他汀类联合疗法的临床翻译 并可能在其他HER2+癌症中得到更广泛的应用。翻译的长期目标是建立 他汀类药物联合曲妥珠单抗预防或推迟药物出现的临床试验的基础 HER2+EG癌患者的耐药性研究

PROJECT SUMMARY/ABSTRACT The incidence of esophagogastric (EG) cancer is increasing rapidly, notably among young men. In patients clinically classified as HER2-positive (ERBB2 amplification and/or 2+/3+ protein overexpression), the combination of the therapeutic anti-HER2 antibody trastuzumab and standard cytotoxic therapy prolongs progression-free and overall survival. However, intrinsic tumor resistance or mechanisms of resistance developed during treatment limit the clinical benefit in 32% of patients, and other anti-HER2 therapeutic antibodies failed in clinical trials to treat EG cancer. Complementary biomarkers and methods are therefore needed to treat such patients. Guided by preclinical data suggesting that caveolin-1 (CAV1) – the main protein of cholesterol-rich invaginations of the plasma membrane – reduces trastuzumab binding to HER2-positive EG tumors, we initiated retrospective clinical analyses to validate CAV1 as a complementary biomarker of HER2. Remarkably, Kaplan-Meier survival analyses demonstrated that HER2+ EG tumors expressing high CAV1 (IHC 2+/3+) had worse overall survival than those expressing low CAV1 (IHC 0/+1) after trastuzumab therapy. These promising preliminary results prompted us to pharmacologically deplete CAV1 (which is present in cholesterol membrane domains) with lovastatin, a cholesterol-depleting drug. Here, we will perform retrospective analyses of patients with HER2-positive EG tumors to assess HER2 expression and heterogeneity, ERBB2 amplification, CAV1 staining and the presence of genetic alterations (copy number variations) associated with trastuzumab resistance. We will analyze medical records to determine if concurrent statin use is associated with enhanced response to trastuzumab. In addition to retrospective analyses, we will perform randomized imaging and therapeutic preclinical studies using patient-derived EG xenografts (PDXs) representing HER2+/CAV1High and HER2+/CAV1Low tumor populations. We will determine the molecular imaging profile (89Zr-Trastuzumab PET) and therapeutic efficacy in PDXs treated with (1) control saline, (2) trastuzumab alone, (3) lovastatin alone, or (4) the combination of trastuzumab with lovastatin, to identify molecular features that confer drug sensitivity and resistance to this promising investigational combination. Aim 1 will validate CAV1 as a complementary biomarker to HER2, Aim 2 will determine the potential dosimetric impact of the statins on clinical imaging and identify EG tumor populations that benefit from the trastuzumab/lovastatin combination, and Aim 3 will validate the use of a statin as a new pharmacologic approach to HER2-targeted imaging and systemic radionuclide therapy (endoradiotherapy) capable of reducing off-target radiation doses. All three aims will generate important new preclinical data on the use of statins to improve trastuzumab efficacy, which should provide an excellent foundation for many future investigations, including clinical translation of trastuzumab/statin combination therapy and potential broader application to other HER2+ cancers. The long-term translational objectives are to establish the foundation for a clinical trial combining statin with trastuzumab to prevent or delay the emergence of drug resistance in patients with HER2+ EG cancer.