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

使用 AcidoCEST MRI 对乳腺癌患者肿瘤酸中毒进行成像的早期临床试验

基本信息

批准号：
8948796
负责人：
Mark David Pagel
金额：
$ 34.99万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-19 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8948796
关键词：
Acidosis Address Aerobic Biological Markers Breast Cancer Patient Chemicals Clinic Clinical Clinical Research Clinical Trials Contrast Media Cyclophosphamide Diagnosis Dose Doxorubicin ERBB2 gene Engineering Ensure Estrogen Receptors Evaluation Glycolysis Histopathologic Grade Hypoxia Image In complete remission Institutional Review Boards Lactic acid Lymphoma MRI Scans Magnetic Resonance Imaging Malignant Neoplasms Maps Measurement Measures Metabolism Methods Modeling Monitor Neoadjuvant Therapy Normal tissue morphology Outcome Paclitaxel Patients Pharmaceutical Preparations Phase Phenotype Protocols documentation Reporting Research Personnel Resected SDZ RAD Testing Therapeutic Tissues Translating Translations Tumor Subtype Warburg Effect arm base cancer imaging carbonate dehydratase chemotherapy extracellular imaging modality improved in vivo innovation lymph nodes mTOR Inhibitor malignant breast neoplasm metaiodobenzylguanidine mouse model non-invasive imaging pre-clinical preclinical study prospective public health relevance receptor expression response standard care tool tumor tumor growth tumor metabolism tumor microenvironment tumor xenograft volunteer

项目摘要

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.

描述（由申请人提供）：我们开发了一种非侵入性成像方法，可以定量测量肿瘤中的细胞外pH值（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”。我们最近将acidoCEST MRI转换为临床3 T MRI扫描仪，我们已经使用我们的方案测试了志愿者，我们的第一次临床试验获得了IRB批准的方案，我们组建了一支非常强大的研究人员团队来进行我们的临床研究。因此，所有步骤都已到位，可以开始我们的临床试验。对于特定的im 1，我们建议将乳腺癌患者的肿瘤pHe与肿瘤亚型和酸中毒、缺氧和糖酵解的离体相关性相关联。我们的理由是基于我们临床前研究的广泛结果，这些研究表明更具侵袭性的肿瘤模型具有更高的肿瘤酸中毒。我们还表明，肿瘤pH与碳酸酐酶IX的高表达相关，碳酸酐酶IX是肿瘤缺氧的既定生物标志物。我们将对乳腺癌患者进行acidoCEST MRI扫描，并在标准护理期间从切除的组织中获得离体相关信息。对于特定目标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。我们的理由是基于我们的临床前成像结果，这些结果显示依维莫司（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，然后在每天治疗7天后恢复到酸性状态，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4周后进行acidoCEST MRI扫描，新辅助化疗采用剂量密集的多柔比星-环磷酰胺，随后是紫杉醇。我们将初始肿瘤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DELIVERABLE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，可用于改善诊断和评估乳腺癌患者对化疗的早期反应。