Optical Imaging of Bladder Cancer with Molecular Contrast Agents

描述(申请人提供)：我们的长期目标是通过基于光学成像的更好的诊断来改善高级别膀胱癌患者的预后。膀胱癌是美国第五大最常见的癌症，2009年有70,980例新病例和14,330例可归因性死亡。除了监测和治疗的相关发病率外，膀胱癌造成的巨大医疗负担使其成为从诊断到死亡治疗费用最高的癌症。目前膀胱癌的诊断标准依赖于白光膀胱镜(WLC)和膀胱镜切除活检的病理确认和局部分期。光学成像质量的好坏直接影响到膀胱癌的诊断、监测、手术及预后。WLC对非乳头状癌和扁平癌的诊断准确率不佳，这些肿瘤很难与先前治疗中共存的炎性病变或疤痕区分开来。值得注意的是，正是这些肿瘤更有可能是高级别、易复发和进展为肌肉侵袭性疾病，通常需要切除膀胱(即根治性膀胱切除术)。我们的总体假设是，膀胱癌的实时分子成像将改善高级别膀胱癌的诊断和治疗。通过将癌症特异性分子造影剂与光学成像工具相结合，我们的目标是提高对高级别膀胱癌的早期检测，以更好地控制局部癌症，促进膀胱癌的保留。为实现这一目标，我们初步开展了以下工作：1)首次应用激光共聚焦显微镜进行活体膀胱镜的临床应用；2)应用噬菌体展示技术和全器官生物扫描技术鉴定膀胱癌结合肽；3)确定CD47是膀胱癌治疗和成像的良好靶点。我们提出了三个具体的目标：(1)鉴定和初步验证多肽和CD47抗体作为膀胱癌特异性分子造影剂；(2)在小鼠原位膀胱癌模型中使用共聚焦激光内窥镜在体内验证分子对比剂；以及(3)使用共聚焦激光内窥镜在完整的人膀胱中验证分子对比剂。为了实现这些目标，我们组建了一个多学科团队，在膀胱癌、分子成像、小动物癌症模型和光学诊断方面具有互补的专业知识。该团队由一名泌尿外科科学家、一名癌症生物学家和一名泌尿外科病理学家组成。我们预计，在这个高度翻译的项目结束时，我们将形成必要的基础，开始在体内验证这些分子造影剂在人类受试者中的应用。

DESCRIPTION (provided by applicant): Our long-term objective is to improve the outcomes of patients with high-grade bladder cancer through better diagnostics based on optical imaging. Bladder cancer is the fifth most common cancer in the United States, with 70,980 new cases and 14,330 attributable deaths in 2009. In addition to the associated morbidity of surveillance and treatment, the enormous healthcare burden imposed by bladder cancer makes it the most expensive cancer to treat from diagnosis to death. The current standard for bladder cancer diagnosis relies on white light cystoscopy (WLC) and cystoscopic excisional biopsy for pathologic confirmation and local staging. The quality of optical imaging directly impacts the diagnosis, surveillance, surgery, and consequently the outcome of bladder cancer. WLC has suboptimal diagnostic accuracy for nonpapillary and flat cancerous tumors, which are challenging to differentiate from co-existing inflammatory lesions or scars from prior treatments. Notably, it is these tumors that are more likely to be high-grade, recurrence-prone, and progressive to muscle-invasive disease, which typically require removal of bladder (i.e. radical cystectomy). Our overall hypothesis is that real-time molecular imaging of bladder cancer will lead to improved diagnosis and therapy of high grade bladder cancer. By coupling cancer-specific molecular contrast agents with optical imaging tools, we aim to improve detection of high-grade bladder cancer at an early stage to effect better local cancer control and promote bladder sparing. Towards this goal, we have preliminarily: 1) performed the first clinical application of intravital microscopy in the bladder using confocal laser endomicroscopy; 2) applied phage display technology and whole organ biopanning to identify bladder cancer-binding peptides; and 3) identified CD47 as a promising therapeutic and imaging target for bladder cancer. We propose three specific aims: (1) identification and preliminary validation of peptides and CD47 antibody as bladder cancer-specific molecular contrast agents; (2) in vivo validation of the molecular contrast agents in a mouse orthotopic bladder cancer model using confocal laser endomicroscopy; and (3) ex vivo validation of the molecular contrast agents in intact human bladders using confocal laser endomicrocopy. To achieve these aims, we have assembled a multidisciplinary team with complementary expertise in bladder cancer, molecular imaging, small animal cancer models, and optical diagnostics. The team is consisted of an urologic surgeon-scientist, a cancer biologist and an urologic pathologist. We anticipate that at the conclusion of this highly translational project, we will have formed the necessary foundation to begin in vivo validation of these molecular contrast agents for application in human subjects.