Diagnosis and longitudinal monitoring of metastatic prostate cancer through molecular MR imaging.

通过分子磁共振成像诊断和纵向监测转移性前列腺癌。

• 批准号: 9755062
• 负责人: Nicole Franziska Steinmetz
• 金额: $ 40.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755062
• 关键词: Accounting; Affinity; American; Antibodies; Binding; Biochemical; Biodistribution; Biological Markers; Blood; CD47 gene; Cancer Patient; Cancer Prognosis; Cancerous; Cells; Cessation of life; Chelating Agents; Chemistry; Clinic; Clinical; Contrast Media; Data; Dependence; Detection; Diagnosis; Disease; Disease Progression; Dose; Early Diagnosis; Engineering; Epithelium; Equilibrium; Exhibits; Gadolinium; Gleason Grade for Prostate Cancer; Histology; Human; Image; Immune; Immune response; Immunoconjugates; Immunofluorescence Immunologic; Indolent; Integrin alpha3beta1; Integrins; Legal patent; Length; Lesion; Ligand Binding; Ligands; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Molecular; Molecular Profiling; Molecular Target; Monitor; Monoclonal Antibodies; Mononuclear; Morbidity - disease rate; Nanotubes; Neoplasm Metastasis; Non-Invasive Cancer Detection; Optics; PSA level; Patients; Peptide antibodies; Peptides; Performance; Phagocytes; Predictive Value; Primary Lesion; Prognostic Factor; Prostate; Prostate Cancer therapy; Prostatectomy; Prostatic Neoplasms; Proteins; Recurrence; Resolution; Risk stratification; Safety; Screening for Prostate Cancer; Shapes; Signal Transduction; Site; Specificity; Stratification; Surface; Survival Rate; System; Technology; Therapeutic Intervention; Time; Tissues; Tobacco Mosaic Virus; Toxic effect; Translations; Tumor stage; Xenograft procedure; advanced disease; base; biomaterial compatibility; cell motility; contrast enhanced; dosage; early screening; follow-up; imaging agent; imaging approach; imaging study; improved; in vivo; men; minimally invasive; molecular imaging; mortality; mouse model; nanoparticle; off-patent; optical imaging; outcome forecast; overtreatment; prognostic tool; prognostic value; prostate cancer model; prostate cancer progression; public health relevance; quantitative imaging; retinal rods; scaffold; serial imaging; small molecule; success; surface coating; targeted agent; targeted imaging; treatment response

 DESCRIPTION (provided by applicant): Improvements in early detection and screening for prostate cancer have benefited patients by reducing cancer- specific mortality and decreasing the number of those that suffer from the complications of advanced disease. Nevertheless, the balancing of early diagnosis with the potential for overtreatment of prostate cancer remains a clinical dilemma. To distinguish between aggressive and indolent disease, we propose a minimally invasive molecular imaging approach to detect integrin-free tetraspanin CD151free. CD151free is a pool of CD151 that arises as a result of a cell migration switch in prostate epithelium. Increased CD151free levels are predictive of early biochemical recurrence and metastasis in prostate cancer patients post-prostatectomy. Histology analysis indicates that CD151free is selectively detected in prostate cancer, and not in healthy prostate glands. Our studies indicate CD151free to be an independent prognostic factor, significantly improving predictive value compared to Gleason grading and PSA level alone. We propose a non-invasive magnetic resonance (MR) imaging approach to detect and monitor CD151free expression to aid prostate cancer prognosis. To achieve sufficient payload delivery and MR contrast enhancement, we propose a molecularly-targeted macromolecular MR probe that we recently developed. The contrast agent carries a large payload of chelated gadolinium Gd (DOTA) and exhibits a T1 of ~35,000 mM-1s-1, which is four orders of magnitude higher than the T1 of current clinical agents. The contrast agent is self-assembled using protein-based, hollow nanotubes formed by tobacco mosaic virus (TMV). The elongated shape of the nanotube enables evasion from the mononuclear phagocyte system and enhances molecular target recognition. Specific targeting to CD151free in cancerous lesions and metastatic sites will be achieved through immunoconjugates and peptide ligands that bind to CD151free with high specificity and affinity. We hypothesize that the CD151free-targeted, shape-optimized contrast agent with high MR signal enhancement will provide sensitive delineation of CD151free expression in primary lesions and occult metastases. Through Aim 1, we will develop a CD151free-specific dual optical-MR probe. Targeted, Gd (DOTA)-loaded contrast agents will be assembled, and target-specificity will be evaluated in dependence of surface coating (stealth coating vs. camouflage) and nanoparticle shape. Aim 2 will focus to determine the in vivo MR imaging parameters in xenograft and metastatic mouse models; targeted MRI enhancement and CD151free-specificity will be validated with optical imaging and histology. Aim 3 sets out to evaluate the utility of our imaging agent in monitoring disease progression and response to treatment longitudinally. Safety of the contrast agents will be evaluated by studying potential immune response, Gd-release and clearance, as well as tissue toxicity. Success in this approach would enable prostate cancer stratification and prognosis as well as follow-up; data indicate correlation of CD151free with aggressiveness of other human malignancies, and therefore this approach may find broad applicability in cancer prognosis.

 描述（由适用提供）：前列腺癌的早期检测和筛查的改善通过降低癌症特定死亡率并减少患有晚期疾病并发症的人数通过减少患者的数量来使患者受益。然而，早期诊断与前列腺癌过度治疗的潜在的平衡仍然是临床困境。为了区分侵略性和惰性疾病，我们提出了一种微创分子成像方法，以检测无整合素的四叠蛋白CD151FROE。 CD151FREE是CD151的池，由于前列腺上皮中的细胞迁移开关而产生。 CD151F的升高水平可预测前列腺癌患者的早期生化复发和转移后切除术后切除术。组织学分析表明，在前列腺癌中选择性检测到CD151FRE，而不是在健康的前列腺腺体中检测到。我们的研究表明，CD151FREE是一个独立的预后因素，与仅Gleason分级和PSA水平相比，预测价值显着提高。我们提出了一种非侵入性磁共振（MR）成像方法，以检测和监测CD151无表达以帮助前列腺癌的预后。为了实现足够的有效载荷交付和MR对比度增强，我们提出了我们最近开发的一个分子靶向的大分子MR探针。对比剂载有大量确认的Gadolinium GD（DOTA）的有效载荷，并表现出约35,000 mm-1s-1的T1，比当前临床剂的T1高四个数量级。对比剂是使用烟草镶嵌病毒（TMV）形成的基于蛋白质的空心纳米管进行自组装的。纳米管的细长形状使单核吞噬细胞系统的进化并增强了分子靶标识别。在取消病变和转移部位的CD151FREE的特定靶向将通过与CD151FROED具有高特异性和亲和力结合的免疫偶联物和肽配体来实现。我们假设，具有高MR信号增强的CD151Free靶向，形状优化的对比剂将在原发性病变和神秘转移酶中对CD151-Free表达的敏感描述。通过AIM 1，我们将开发CD151F的特异性双光学MR探针。将组装有针对性的GD（DOTA）对比度，并将评估目标特异性，以依赖于表面涂层（隐形涂层与伪装）和纳米颗粒形状。 AIM 2将集中精力确定分类和转移小鼠模型中的体内MR成像参数；有针对性的MRI增强和CD151Free特异性将通过光学成像和组织学验证。 AIM 3旨在评估我们的成像剂在监测疾病进展和纵向治疗反应方面的效用。对比剂的安全性将通过研究潜在的免疫反应，GD释放和清除率以及组织毒性来评估。这种方法的成功将使前列腺癌的分层和预后以及随访。数据表明CD151FRE与其他人类恶性肿瘤的侵略性的相关性，因此这种方法可能在癌症预后中发现广泛的适用性。