Progesterone Contrast Agents for MRI

描述（由申请人提供）：孕酮是一种类固醇激素，与其受体结合，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。PR在90%的良性和I级乳腺肿瘤中表达，通常在不到20%的侵袭性和浸润性癌症中发现。低级别子宫内膜癌表达孕激素受体，受体丢失与预后不良相关。确定乳腺或子宫内膜肿瘤激素受体状态的非侵入性方法将确定治疗方案，确定肿瘤的大小和确切位置，并在传统成像策略错过或混淆病变时提供检测癌症的额外工具。目前很少有方法可用于体内乳腺和子宫内膜肿瘤的成像，这些药物都不能促进肿瘤的分子或治疗谱。这是该资助提案的论点，钆（III）结合孕酮造影剂可以靶向激素受体阳性细胞，并用于非侵入性成像乳腺和子宫内膜肿瘤大小和受体状态，并改善治疗决策。我们的初步研究已经确定钆（Gd）共轭孕酮化合物能够穿越细胞膜，结合孕酮受体，启动基因转录，并提高对比度的哺乳动物细胞成像使用磁共振。这些代理商中最有前途的被称为“ProGlow。该提案的重点是ProGlow的应用，以增强类固醇受体肿瘤和组织在体内的成像。具体目标1将研究是否可以使用ProGlow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。具体目标2重点关注ProGlow不仅用于乳腺癌，还用于子宫癌。Specific Aim 3将提出一系列策略，以增加靶组织的弛豫率和特异性，从而改善ProGlow用于使用MRI进行靶向分子分析。癌症诊断中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志物。ProGlow是这个问题的一个可能的解决方案，因为它将允许非侵入性诊断，分子表征和治疗决定与胆固醇相关的癌症。 公共卫生相关性：乳腺癌和子宫内膜癌的分子标志物的测定是必要的，因为这些标志物决定了患者的预后和治疗方案，但这需要侵入性活检，这是痛苦的，并且由于只使用肿瘤的一小部分而容易出错。该研究开发了癌症靶向磁共振成像造影剂，可用于非侵入性诊断和分子表征整个肿瘤和转移，以改善治疗决策并监测这些疾病和复发。

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.