Guiding Ca2+ Channel-Based Cancer Treatment Using Mn2+-Enhanced MRI

使用 Mn2 增强 MRI 指导基于 Ca2 通道的癌症治疗

基本信息

批准号：
8486938
负责人：
RODNEY D BRAUN
金额：
$ 16.53万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8486938
关键词：
Address Agonist Agreement Antineoplastic Agents Apoptosis Biological Assay Biological Markers CaT1 calcium channel Calcium Channel Calcium Signaling Calcium ion Cancer cell line Cell Line Cell membrane Cells Colorectal Cancer Contrast Media Development Drug Targeting Genetic Transcription Goals Human In Vitro Individual Injection of therapeutic agent Ion Channel Ions Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Manganese Measures Metabolism Methods Molecular Profiling Nature Outcome Patients Pharmaceutical Preparations Phase I Clinical Trials Proteins Relaxation SCID Mice Testing Therapeutic Tissues Treatment-Related Cancer Tumor Cell Line Western Blotting Xenograft procedure base cancer cell cancer therapy cancer type clinically relevant in vivo innovation innovative technologies malignant breast neoplasm manganese chloride neoplastic cell novel strategies protein expression public health relevance receptor research study response subcutaneous therapeutic target tissue culture tumor tumor xenograft uptake voltage

项目摘要

DESCRIPTION (provided by applicant): Certain calcium ion (Ca2+) channels, e.g., voltage-gated (VGCC) and transient receptor potential (TRP) Ca2+ channels, are highly expressed in some cancers, suggesting that they could be therapeutic targets. Indeed, drugs specifically targeting subclasses of these channels already exist and two are currently in Phase I clinical trials, but it is difficult to unravel which specific channel to target in individual tumors. Our lng-term goal is to develop an analytical, non-invasive assay of tumor calcium channel activity in vivo that could eventually be used clinically as a means to individualize Ca2+ channel-targeted therapies. To achieve this goal, we will measure tumor uptake of manganese ion (Mn2+), an MRI contrast agent that largely enters cells via Ca2+ channels. Our preliminary studies show that on manganese-enhanced MRI (MEMRI) examination, different types of human cancer cells take up exogenous Mn2+ in a calcium channel dependent fashion, resulting in an increase in MRI longitudinal relaxation rates, i.e., R1 values. In addition, specific and systemically administered agonists and antagonists of VGCC channels modify non-tumor tissue Mn2+ accumulation in vivo. The overall hypothesis of this proposal is that the extent of tumor uptake of Mn2+ in the presence of Ca2+ channel-specific agonists or antagonists, measured using manganese enhanced MRI (MEMRI), is a useful biomarker of specific calcium channel activity in the tumor and thus a rational approach for predicting potential tumor therapeutic response to Ca2+ channel-based therapies. To fully test this hypothesis, we will address two specific aims. In Aim 1, we will define the sensitivity of MEMRI and specific Ca2+ channel modulation as a method to identify the predominant Ca2+ channels expressed in different types of human tumor cells in vitro. We will characterize the prevalent Ca2+ channels in various human tumor cell lines using Western blots, treat the different cells with agonists and antagonists to specific Ca2+ channels, and then measure Mn2+ uptake in each cell line using MEMRI. The prediction is that specific agonists and/or antagonists will change the cellular R1 values, thereby identifying the key channel(s) expressed by the specific tumor cells. In Aim 2, we will determine if the combination of MEMRI and specific Ca2+ channel modifiers can identify dominant Ca2+ channel types in different human tumor xenografts in vivo. Based on the in vitro studies, selected agonists and antagonists will be injected into SCID mice bearing subcutaneous human xenografts, and average R1 values will be determined in the tumors following MnCl2 injection. The prediction is that injection of specific agonists and/or antagonists will change the tumor R1 values, thereby identifying the key Ca2+ channel(s) expressed by the specific xenografts. We envision that the combined use of MEMRI and modulation of specific Ca2+ channel activity will eventually be useful to noninvasively determine whether a targeted Ca2+ channel is expressed in a patient's tumor, thereby guiding subsequent Ca2+ channel-based treatment.

描述（由申请人提供）：某些钙离子（Ca2+）通道，例如电压门控（VGCC）和瞬时受体电位（TRP）Ca2+通道，在一些癌症中高度表达，表明它们可能是治疗靶点。事实上，专门针对这些通道子类的药物已经存在，并且目前有两种正处于 I 期临床试验中，但很难弄清楚针对个体肿瘤的特定通道。我们的长期目标是开发一种分析性、非侵入性的体内肿瘤钙通道活性测定方法，最终可以在临床上用作个体化 Ca2+ 通道靶向治疗的手段。为了实现这一目标，我们将测量肿瘤对锰离子 (Mn2+) 的摄取，锰离子是一种 MRI 造影剂，主要通过 Ca2+ 通道进入细胞。我们的初步研究表明，在锰增强磁共振成像（MEMRI）检查中，不同类型的人类癌细胞以钙通道依赖性方式吸收外源性Mn2+，导致MRI纵向弛豫率（即R1值）增加。此外，具体和系统的管理 VGCC 通道的激动剂和拮抗剂可改变体内非肿瘤组织 Mn2+ 的积累。该提案的总体假设是，在 Ca2+ 通道特异性激动剂或拮抗剂存在的情况下，使用锰增强 MRI (MEMRI) 测量的肿瘤摄取 Mn2+ 的程度，是肿瘤中特定钙通道活性的有用生物标志物，因此预测基于 Ca2+ 通道的疗法的潜在肿瘤治疗反应的合理方法。为了充分检验这一假设，我们将解决两个具体目标。在目标 1 中，我们将定义 MEMRI 的敏感性和特定 Ca2+ 通道调制作为识别体外不同类型人类肿瘤细胞中表达的主要 Ca2+ 通道的方法。我们将使用蛋白质印迹来表征各种人类肿瘤细胞系中普遍存在的 Ca2+ 通道，用特定 Ca2+ 通道的激动剂和拮抗剂处理不同的细胞，然后使用 MEMRI 测量每个细胞系中 Mn2+ 的摄取。预测特定激动剂和/或拮抗剂将改变细胞 R1 值，从而识别特定肿瘤细胞表达的关键通道。在目标 2 中，我们将确定 MEMRI 和特定 Ca2+ 通道修饰剂的组合是否可以识别体内不同人类肿瘤异种移植物中的主要 Ca2+ 通道类型。根据体外研究，将选定的激动剂和拮抗剂注射到皮下人类异种移植物的 SCID 小鼠中，并在注射 MnCl2 后测定肿瘤中的平均 R1 值。预测是注射特定的激动剂和/或拮抗剂将改变肿瘤 R1 值，从而识别特定异种移植物表达的关键 Ca2+ 通道。我们设想，MEMRI 和特定 Ca2+ 通道活性调节的结合使用最终将有助于无创地确定目标 Ca2+ 通道是否在患者的肿瘤中表达，从而指导后续基于 Ca2+ 通道的治疗。