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（由申请人提供）：前列腺癌早期检测和筛查的改进通过降低癌症特异性死亡率和减少患有晚期疾病并发症的人数而使患者受益。然而，早期诊断与潜在疾病的平衡仍然存在。前列腺癌的过度治疗仍然是一个临床难题，为了区分侵袭性疾病和惰性疾病，我们提出了一种微创分子成像方法来检测无整合素四跨膜蛋白 CD151free。由于前列腺上皮细胞迁移转换而产生的 CD151 水平升高可预测前列腺癌患者前列腺切除术后的早期生化复发和转移。我们的研究表明 CD151free 是一个独立的预后因素，与单独的格里森分级和 PSA 水平相比，显着提高了预测价值。磁共振 (MR) 成像方法检测和监测 CD151free 表达，以帮助前列腺癌预后。为了实现足够的有效负载输送和 MR 对比度增强，我们提出了一种我们最近开发的分子靶向大分子 MR 探针，该探针携带大量有效负载。螯合钆 Gd (DOTA) 的 T1 约为 35,000 mM-1s-1，比当前临床药物的 T1 高四个数量级。该试剂是使用由烟草花叶病毒 (TMV) 形成的基于蛋白质的中空纳米管进行自组装的，纳米管的细长形状能够逃避单核吞噬细胞系统，并增强对癌性病变和转移部位中无 CD151 的分子靶标识别。将通过以高特异性和亲和力与 CD151free 结合的免疫缀合物和肽配体来实现，我们捕获了 CD151free 靶向的、形状优化的。具有高 MR 信号增强的造影剂将提供原发性病变和隐匿性转移灶中无 CD151 表达的灵敏描绘，我们将开发一种无 CD151 特异性双光学 MR 探针，该探针将负载 Gd (DOTA)。目标特异性将根据表面涂层（隐形涂层与伪装）进行评估，目标 2 将重点确定纳米粒子的形状。异种移植和转移小鼠模型中的体内 MR 成像参数；目标 MRI 增强和 CD151-free 特异性将通过光学成像和组织学进行验证，目的是评估我们的成像剂在纵向监测疾病进展和治疗反应方面的效用。将通过研究潜在的免疫反应、Gd 释放和清除以及组织毒性来评估造影剂的效果，该方法的成功将使前列腺癌分层和预后以及后续数据表明相关性； CD151free 与其他人类恶性肿瘤的侵袭性相比，因此这种方法可能在癌症预后中具有广泛的适用性。