Progesterone Contrast Agents for MRI

描述（由申请人提供）：孕酮是一种类固醇激素，与受体结合，并在细胞核中作为转录因子发挥作用，在细胞核中与DNA中的孕酮反应元件结合。孕激素受体（PR）在90%的良性和I级乳腺肿瘤中表达，在不到20%的侵袭性和侵袭性癌症中发现。低级别子宫内膜癌表达孕激素受体，受体缺失与预后不良相关。一种检测乳腺或子宫内膜肿瘤激素受体状态的非侵入性方法将决定治疗方案，确定肿瘤的大小和确切位置，并在传统成像策略遗漏或混淆病变时提供检测癌症的额外工具。目前用于乳腺和子宫内膜肿瘤体内成像的方法很少，而且这些药物都不能促进肿瘤的分子或治疗谱。本课题的主题是钆（III）偶联孕酮造影剂可以靶向激素受体阳性细胞，对乳腺和子宫内膜肿瘤的大小和受体状态进行无创伤成像，从而改善治疗决策。我们的初步研究已经确定钆（Gd）偶联孕酮化合物能够穿过细胞膜，结合孕酮受体，启动基因转录，并增强哺乳动物细胞磁共振成像的对比度。这些药物中最有前途的被称为“ProGlow”。本课题的重点是应用ProGlow增强体内类固醇受体肿瘤和组织的成像。特异性目的1将研究使用ProGlow是否可以将异种移植肿瘤分类为孕酮受体阳性，以及是否可以量化肿瘤体积的变化。特异性目标2重点介绍ProGlow在乳腺癌和子宫癌中的应用。Specific Aim 3将提出一系列策略来增加目标组织的弛豫性和特异性，以改进ProGlow用于MRI靶向分子分析。癌症诊断的一个关键问题是在不进行侵入性活检的情况下确定影响治疗和预后的分子标记。ProGlow可能是解决这一问题的方法，因为它将允许对孕激素相关癌症进行无创诊断、分子表征和治疗确定。

DESCRIPTION (provided by applicant): Progesterone is a steroid hormone that binds to its receptor and functions as a transcription factor in the nucleus where it binds to progesterone responsive elements in the DNA. Progesterone receptors (PR) are expressed in 90% of benign and grade I breast tumors and are typically found in less than 20% of aggressive and invasive cancers. Low grade endometrial cancers express progesterone receptor, and loss of receptor is associated with poor prognosis. A non-invasive means of determining the hormone receptor status of breast or endometrial tumors would determine treatment options, identify the size and exact location of the tumor, and provide an additional tool for detecting cancer when traditional imaging strategies miss or confuse lesions. Few methods are currently available for imaging breast and endometrial tumors in vivo and none of these agents facilitate the molecular or therapeutic profiling of the tumor. It is the thesis of this grant proposal that gadolinium(III) conjugated progesterone contrast agents can target hormone receptor positive cells and function to non-invasively image breast and endometrial tumor size and receptor status and improve treatment decisions. Our preliminary studies have identified gadolinium (Gd) conjugated progesterone compounds as capable of traversing the cell membrane, binding to progesterone receptors, initiating gene transcription, and enhancing contrast in mammalian cells imaged using magnetic resonance. The most promising of these agents is termed "ProGlow. This proposal focuses on the application of ProGlow to enhance the imaging of steroid receptor tumors and tissues in vivo. Specific Aim 1 will investigate if xenografted tumors can be classified as progesterone receptor positive using ProGlow and if changes in tumor volume can be quantified. Specific Aim 2 focuses on the application of ProGlow not only for breast but also uterine cancers. Specific Aim 3 will present a series of strategies to increase relaxivity and specificity for targeted tissues to improve ProGlow for targeted molecular profiling using MRI. A critical problem in cancer diagnosis is the determination of molecular markers that influence treatment and prognosis without performing invasive biopsies. ProGlow is a possible solution to this problem in that it will allow for noninvasive diagnosis, molecular characterization, and treatment determination of progesterone-related cancers. PUBLIC HEALTH RELEVANCE: The determination of molecular markers in breast and endometrial cancers is necessary because these markers decide the prognosis and treatment options for patients, but this requires invasive biopsies that are painful and subject to error due to the use of only small portions of a tumor. The proposed research develops cancer-targeted magnetic resonance imaging contrast agents that can be used to noninvasively diagnose and molecularly characterize entire tumors and metastases in order to improve treatment decisions and monitor these diseases and recurrences.