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

项目总结/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。在临床上 分类为HER 2阳性（ERBB 2扩增和/或2+/3+蛋白过表达）， 治疗性抗HER 2抗体曲妥珠单抗和标准细胞毒性治疗无进展和总体 生存然而，内在的肿瘤抗性或在治疗过程中产生的抗性机制限制了肿瘤的治疗。 32%的患者有临床获益，其他抗HER 2治疗性抗体在治疗EG的临床试验中失败 癌因此，需要补充的生物标志物和方法来治疗这些患者。临床前指导 数据表明，小窝蛋白-1（CAV 1）-质膜富含胆固醇的内陷的主要蛋白质 - 减少曲妥珠单抗与HER 2阳性EG肿瘤的结合，我们启动了回顾性临床分析，以验证 CAV 1作为HER 2的互补生物标志物。值得注意的是，Kaplan-Meier生存分析表明， 表达高CAV 1（IHC 2+/3+）的HER 2 + EG肿瘤的总生存期比表达低CAV 1的肿瘤差 (IHC 0/+1）。这些有希望的初步结果促使我们 用洛伐他汀（一种胆固醇消耗药物）消耗CAV 1（存在于胆固醇膜结构域中）。 在此，我们将对HER 2阳性EG肿瘤患者进行回顾性分析，以评估HER 2表达 和异质性，ERBB 2扩增，CAV 1染色和遗传改变（拷贝数）的存在 变异）与曲妥珠单抗耐药性相关。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对曲妥珠单抗的反应增强有关。除了回顾性分析，我们还将 使用患者来源的EG异种移植物（PDX）进行随机成像和治疗临床前研究 代表HER 2 +/CAV 1高和HER 2 +/CAV 1低肿瘤群体。我们将通过分子成像 （1）对照生理盐水，（2）曲妥珠单抗治疗的PDX中的特征（89 Zr-曲妥珠单抗PET）和疗效 单独使用，（3）单独使用洛伐他汀，或（4）曲妥珠单抗与洛伐他汀的组合，以鉴定 赋予药物敏感性和对这种有前景的研究组合的抗性。目标1将验证CAV 1作为 作为HER 2的补充生物标志物，Aim 2将确定他汀类药物对临床治疗的潜在剂量学影响。 成像和识别从曲妥珠单抗/洛伐他汀联合治疗中获益的EG肿瘤人群，Aim 3将 验证他汀类药物作为HER 2靶向成像和全身放射性核素的新药理学方法的用途 能够减少脱靶放射剂量的治疗（腔内放射治疗）。这三个目标将产生重要的 关于使用他汀类药物改善曲妥珠单抗疗效的新临床前数据，这将提供一个极好的 为许多未来研究奠定基础，包括曲妥珠单抗/他汀类药物联合治疗的临床转化 并可能更广泛地应用于其他HER 2+癌症。长期目标是建立 为他汀类药物与曲妥珠单抗联合预防或延迟药物出现的临床试验奠定了基础 HER 2 + EG癌症患者的耐药性。

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.