TRANSRECTAL ULTRASOUND AND PHOTOACOUSTIC IMAGING OF PROSTATE AND MOLECULAR IMAGIN

描述(申请人提供)：前列腺癌被过度诊断和过度治疗，挑战了当前的标准筛查实践：经直肠超声(TRUS)引导的随机活检后进行前列腺特异性抗原(PSA)的血液筛查[1-2]。TRUS缺乏可靠的影像特征来区分良性和恶性前列腺组织。它目前的作用仅限于指导随机的针吸活组织检查和估计前列腺体积[3]。2012年5月，美国预防服务工作组(USPSTF)建议不要进行常规的PSA筛查，理由是太多的非致命性癌症正在积极接受治疗，潜在的好处没有超过危害。尽管有这些建议，前列腺癌仍可能表现出侵袭性，转移并导致男性死亡，前列腺癌是美国男性癌症死亡的第二大原因就是明证。成像可以改变前列腺癌的治疗，通过显示目标肿瘤来进行更准确的活检，以便更好地评估分级，并允许临床医生估计肿瘤体积。因此，任何能够描绘前列腺癌肿瘤的成像策略都将是评估前列腺癌侵袭性的重要一步。因此，成像可以通过提高选择男性进行主动监测、手术或放射治疗的信心来改善护理。此外，准确地描绘出 前列腺内的肿瘤可能为局部前列腺癌的治疗开辟新的途径，如局部治疗，以及允许监测治疗反应最近对大量患者的组织病理学样本的研究表明，前列腺癌是血管生成的，侵袭性肿瘤的横截面往往是细小且不规则的，而惰性肿瘤的血管正常[8]。在Sanjiv Gambhir博士实验室的博士后研究工作中，我证明了光声成像(PAI)可以使用前列腺癌小鼠(PCM)模型可靠地成像前列腺癌肿瘤的血管生成。由于我研究的主要目标是临床翻译，在我的合作导师B.T.Khuri-Yakub博士的超声实验室工作，我进一步开发了一种新型前列腺成像设备：使用自制二维(2D)电容式微机械超声换能器(CMUT)阵列的组合实时三维(RT3D)经直肠超声和光声(TRUSPA)设备。这些发现为新的双模式成像策略提供了希望，可以为前列腺癌的筛查和治疗提供新的诊断和预后见解。在这里，我建议将我之前在光学、超声和生物医学工程方面的培训与癌症分子成像方面的新培训相结合，开发临床级别的rt3D TRUSPA成像系统，并进一步研究其作为诊断和预后筛查工具的应用。在目标1(K99阶段)，在数学、计算机模拟和设计工具的帮助下，我将优化和设计TRUSPA设备的不同组件，以在超声和PA模式下可靠地成像到人体前列腺后表面(距离直肠壁4厘米至5厘米)的深处。在AIM 2A(桥接K99/R00期)中，我将系统地研究前列腺癌的血管(血管生成)、功能(与缺氧相关)、代谢和分子(前列腺癌中高表达的靶分子)的特征，以建立定量成像指标，这些指标有可能在PCM模型中使用双模式超声和光声成像技术可靠地预测癌症的诊断和预后特征。在AIM 2B(R00阶段)，我将结合AIMS 1和A的成功成像策略，完成临床级别的rt3D TRUSPA双模式成像系统。超声模式将提供前列腺的解剖/结构信息，包括高回声和低回声区域，而PA模式将利用Aim2A成功的血管、功能和分子成像指标提供前列腺的光学对比。假设这些指标可以可靠地显示癌症的诊断和预后特征。这些临床前研究将帮助我们进一步调整具有临床成功潜力的rt3D Trupa成像策略。这份向独立过渡的提案描述了研究和职业发展活动，包括参加会议和课程培训，这些活动将使我成为独立教员职位的有竞争力的候选人，并帮助我在生物医学工程和癌症分子成像领域发展一个创新的、成功的多学科研究计划，特别关注阐明前列腺癌发展的机制及其对治疗的反应。这些活动将由Butrus的Sanjiv Gambhir博士(斯坦福大学放射学分子成像项目首席导师)指导。T.Khuri-Yakub(电机工程系联合导师，超声成像和CMUT阵列设计与制造专家)，Juergen Willman(放射科联合导师，超声分子成像和犬前列腺癌模型专家)，James D.Brooks(泌尿系联合导师，前列腺癌临床管理、临床试验、成像和生物标记物开发专家)和Joseph C.Liao(泌尿系联合导师，泌尿外科医生，技术验证专家)。

DESCRIPTION (provided by applicant): Prostate cancer is over-diagnosed and over-treated, challenging the current standard screening practice: transrectal ultrasound (TRUS) guided random biopsy following blood screening for prostate specific antigen (PSA) [1-2]. TRUS lacks reliable imaging characteristics that differentiate between benign and malignant prostate tissue. Its role is currently restricted to guide random needle biopsies and estimate prostate volume [3]. In May 2012, the United States Preventive Services Task Force (USPSTF) recommended against routine PSA screening, with the rationale that too many non-lethal cancers were being treated aggressively and that the potential benefits do not outweigh the harms. Despite these recommendations, there are prostate cancers that can behave aggressively, and metastasize and kill men, evidenced by prostate cancer's position as the second leading cause of male cancer death in the US. Imaging could change prostate cancer care by allowing for more accurate biopsies by showing the target tumor so that grade is better assessed and allowing clinicians to estimate tumor volume. Therefore any imaging strategy that allows delineation for the tumors in the prostate would be a major step forward in estimating the aggressiveness of prostate cancer. Imaging could therefore improve care by improving confidence in selecting men for active surveillance, surgery or radiation therapy. In addition, accurate delineation of the tumor within the prostate could open avenues for new approaches to the management of localized prostate cancer such as focal therapy, as well as allowing monitoring of response to therapies Recent study on histopathology specimens of a large cohort of patients demonstrated that prostate tumors are angiogenic, and aggressive tumors tend to have blood vessels that are small and irregular in cross-section, while indolent tumors have normal blood vessels [8]. In my postdoctoral research work in the laboratory of Dr. Sanjiv Gambhir, I have demonstrated that photoacoustic imaging (PAI) can reliably image angiogenesis of prostate tumors using prostate cancer mice (PCM) models. Since the main goal of my research is clinical translation, working in the ultrasound laboratory of my co-mentor Dr. B.T. Khuri-Yakub, I have further developed a novel prostate imaging device: a combined real time three dimensional (rt3D) transrectal ultrasound and photoacoustic (TRUSPA) device using home built two dimensional (2D) capacitive micromachined ultrasound transducer (CMUT) arrays. These findings offer promise for novel dual modality imaging strategy that could provide new diagnostic and prognostic insights into prostate cancer screening and treatment. Here, I propose to merge my prior training in optical, ultrasound and biomedical engineering with new training in molecular imaging of cancer to develop a clinical grade rt3D TRUSPA imaging system and further investigate its use as a diagnostic as well as prognostic screening tool. In Aim 1 (K99 phase), with the help of mathematical, computer simulation and design tools, I will optimize and engineer different components of TRUSPA device to reliably image deep into the posterior surface (4 cm to 5 cm from the rectal wall) of human prostate in both ultrasound and PA modes. In Aim 2A (bridging K99/R00 phases), I will systematically investigate vascular (angiogenesis), functional (hypoxia related), metabolic and molecular (targeting molecules highly expressed in prostate cancer) signatures of prostate cancer to establish quantitative imaging metrics that have potential to reliably predict diagnostic and prognostic features of the cancer using dual modality ultrasound and photoacoustic imaging strategies in PCM models. In Aim 2B (R00 phase), I will accomplish a clinical grade rt3D TRUSPA dual modality imaging system by integrating successful imaging strategies of Aims 1 and 2A. While ultrasound mode will provide anatomical/structural information of the prostate including hyper and hyopoechoic regions, PA mode will provide optical contrast of the prostate leveraging on successful vascular, functional and molecular imaging metrics of Aim2A. The hypothesis is that these metrics can reliably image diagnostic and prognostic features of the cancer. These pre-clinical studies will help us further fine tune rt3D TRUPA imaging strategies that has potential to succeed in clinic. This Transition to Independence proposal describes research and career development activities, including conference attendance and course training that will establish me as a competitive candidate for an independent faculty position and aid my development of an innovative, successful multidisciplinary research program in biomedical engineering and cancer molecular imaging with particular focus on elucidating mechanisms of prostate cancer development and its response to therapy. These activities will be mentored by Drs. Sanjiv Gambhir (primary mentor, Molecular Imaging Program at Stanford, Radiology), Butrus. T. Khuri-Yakub (co-mentor, Electrical Engineering Dept., expert in ultrasound imaging and CMUT array design and fabrication), Juergen Willman (co-mentor, Radiology Dept., expert in ultrasound molecular imaging and canine prostate cancer models), James D. Brooks (co-mentor, Urology Dept., expert in clinical prostate cancer management, clinical trials, imaging and biomarker development) and Joseph C. Liao (co-mentor, Urology Dept., urologic surgeon and expert in technology validation) at Stanford University, which is a world-class research institute for engineering and cancer molecular imaging.