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）和瞬态受体电位（TRP）Ca2+通道，在某些癌症中高度表达，这表明它们可以是治疗靶标。实际上，专门针对这些通道子类的药物已经存在，目前有两种正在进行I期临床试验，但是很难揭示哪个特定的通道在单个肿瘤中靶向。我们的LNG期限目标是开发体内肿瘤钙通道活性的分析，非侵入性测定，最终可以在临床上用作个性化CA2+ CANCH靶标疗法的一种手段。为了实现这一目标，我们将测量锰离子（MN2+）的肿瘤吸收，这是一种MRI对比剂，在很大程度上通过Ca2+通道进入细胞。我们的初步研究表明，在锰增强的MRI（MEMRI）检查中，不同类型的人类癌细胞以钙通道依赖于钙通道的外源MN2+，从而导致MRI纵向松弛率的提高，即R1值。另外，特定和系统地管理 VGCC通道的激动剂和拮抗剂修饰了体内非肿瘤组织MN2+积累。该提议的总体假设是，使用锰增强的MRI（MEMRI）测量的Ca2+通道特异性激动剂或拮抗剂在存在下MN2+的肿瘤摄取程度是肿瘤特定钙通道活性的有用的生物标志物，因此可以预测潜在的plimor themor Themor Themor Themor Themor Therape Theraphe Theraphe Theraphe therapetic the Cailly taill-Channel tailby tailby tailby thec2+ CANC2+ CANC2+ CANTIES。为了充分检验这一假设，我们将解决两个具体目标。在AIM 1中，我们将定义MEMRI和特定Ca2+通道调制的灵敏度，以确定在不同类型的人类肿瘤细胞体外表达的主要Ca2+通道的方法。我们将使用Western印迹在各种人类肿瘤细胞系中表征普遍的Ca2+通道，用激动剂和拮抗剂将不同的细胞与特定的Ca2+通道一起处理，然后使用MEMRI在每个细胞系中测量MN2+摄取。预测是特定的激动剂和/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AIM 2中，我们将确定MEMRI和特定CA2+通道修饰符的组合是否可以在体内识别不同人类肿瘤异种移植物中的显性Ca2+通道类型。基于体外研究，选定的激动剂和拮抗剂将被注入带有皮下人异种移植的SCID小鼠，并在MNCL2注射后的肿瘤中确定平均R1值。预测是注入特定的激动剂和/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的联合使用和特定CA2+通道活性的调节最终将对非侵入性确定是否在患者的肿瘤中表达靶向的Ca2+通道，从而指导后来的CA2+基于CANCH的治疗。