Optical Imaging of Bladder Cancer with Molecular Contrast Agents

描述（由申请人提供）：我们的长期目标是通过基于光学成像的更好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常见癌症，2009年有70,980例新发病例和14,330例可归因于死亡。除了监测和治疗的相关发病率外，膀胱癌带来的巨大医疗负担使其成为从诊断到死亡治疗最昂贵的癌症。目前膀胱癌的诊断标准依赖于白光膀胱镜（WLC）和膀胱镜切除活检进行病理确认和局部分期。光学成像的质量直接影响膀胱癌的诊断、监测、手术，进而影响预后。WLC对非乳头状癌和扁平癌的诊断准确性不理想，这类肿瘤很难与共存的炎性病变或既往治疗留下的疤痕区分开来。值得注意的是，这些肿瘤更可能是高级别、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有助于提高高级别膀胱癌的诊断和治疗。通过肿瘤特异性分子造影剂与光学成像工具的结合，我们旨在提高膀胱癌的早期发现，从而更好地控制局部肿瘤，促进膀胱保护。为此，我们进行了初步的研究：1)首次在膀胱内共聚焦激光内镜下进行了活体显微检查的临床应用；2)应用噬菌体展示技术和全器官生物筛选技术鉴定膀胱癌结合肽；3)发现CD47是膀胱癌的一个有前景的治疗和成像靶点。我们提出了三个具体目标：(1)鉴定和初步验证肽和CD47抗体作为膀胱癌特异性分子造影剂；(2)利用共聚焦激光内镜对分子造影剂在小鼠原位膀胱癌模型中的体内验证；(3)利用激光共聚焦显微内镜对分子造影剂在完整人膀胱中的体外验证。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。该小组由一名泌尿外科医生、一名癌症生物学家和一名泌尿病理学家组成。我们预计，在这个高度转化的项目结束时，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. PUBLIC HEALTH RELEVANCE: Our long-term objective is to improve the outcomes of patients with bladder cancer through better imaging diagnostics. We propose to develop bladder cancer-specific molecular contrast agents for rapid, specific diagnosis of clinically aggressive bladder cancer.