Early phase clinical trial for imaging tumor acidosis in breast cancer patients using acidoCEST MRI

 描述(申请人提供)：我们开发了一种非侵入性成像方法，可以定量测量肿瘤细胞外pH(Phe)。我们的MRI方法使用化学交换饱和转移(CEST)MRI来评估肿瘤酸中毒，称为“ACIDoCEST MRI”。我们最近已经将acidoCEST MRI转换为临床3T MRI扫描仪，我们已经使用我们的方案对志愿者进行了测试，我们已经为我们的第一次临床试验批准了IRB方案，我们还组建了一支非常强大的研究团队来执行我们的临床研究。因此，所有步骤都已就绪，可以开始临床试验。对于特定的IM1，我们建议将乳腺癌患者的肿瘤Phe与肿瘤亚型以及酸中毒、缺氧和糖酵解的体外相关性联系起来。我们的理论基础是基于我们临床前研究的广泛结果，这些结果表明更具侵袭性的肿瘤模型有更高的肿瘤酸中毒。我们还表明，肿瘤Phe与碳酸氢酶IX的高表达有关，碳酸氢酶IX是肿瘤缺氧的既定生物标记物。我们将对乳腺癌患者进行acidoCEST MRI扫描，并在他们的标准护理期间从切除的组织中获得体外相关性。对于特定的目的2，我们建议使用acidoCEST MRI来监测乳腺癌患者对新辅助化疗的早期反应。我们的理论是基于我们的临床前成像结果，这些结果表明Everolimus(一种mTOR抑制剂)如何在开始治疗的1天内提高淋巴瘤模型中的肿瘤Phe，然后在每日治疗7天后返回酸性状态，这预示着这种药物治疗的暂时肿瘤生长延迟。我们将在开始新辅助化疗前和开始后4周进行ACID-CEST MRI扫描，用剂量密集的阿霉素-环磷酰胺，然后是紫杉醇。我们将肿瘤初始Phe和肿瘤Phe的变化与临床结果相关联。基于这些结果，我们的成果是一种创新的非侵入性成像方法，可以生成肿瘤Phe的参数图，可以用于提高乳腺癌患者的诊断和评估化疗的早期疗效。

 DESCRIPTION (provided by applicant): We have developed a non-invasive imaging method that can quantitatively measure the extracellular pH (pHe) in tumors. Our MRI method uses Chemical Exchange Saturation Transfer (CEST) MRI to assess tumor acidosis, termed "acidoCEST MRI". We have recently translated acidoCEST MRI to a clinical 3T MRI scanner, we have tested volunteers with our protocol, we have an approved IRB protocol for our first clinical trial, and we have assembled an exceptionally strong team of investigators to perform our clinical studies. Therefore, all steps are in place to start our clinical trials. For Specific im 1, we propose to correlate tumor pHe in breast cancer patients with tumor subtype and ex vivo correlates of acidosis, hypoxia, and glycolysis. Our rationale is based on our extensive results from our pre-clinical studies that have shown how more aggressive tumor models have a higher tumor acidosis. We have also shown that tumor pHe is correlated with high expression of carbonic anhydrase IX, which is an established biomarker of tumor hypoxia. We will perform acidoCEST MRI scans with breast cancer patients, and obtain ex vivo correlates from resected tissues during their standard care. For Specific Aim 2, we propose to use acidoCEST MRI to monitor the early response to neoadjuvant chemotherapy in breast cancer patients. Our rationale is based on our pre-clinical imaging results that have shown how Everolimus (an mTOR inhibitor) raises tumor pHe in a lymphoma model within 1 day of initiating therapy, and then returns to an acidic state after 7 days of daily treatment, which foreshadowed the temporary tumor growth delay of this drug treatment. We will perform acidoCEST MRI scans before and 4 weeks after initiating neoadjuvant chemotherapy with dose dense doxorubicin-cyclophosphamide followed by paclitaxel. We will correlate initial tumor pHe and the change in tumor pHe with clinical outcome. Based on these results, our DELIVERABLE is an innovative, noninvasive imaging method that can generate parametric maps of tumor pHe, which can be used to improve diagnosis and evaluate early response to chemotherapy for breast cancer patients.