Clinical Translation of dual-modality transrectal ultrasound and photoacoustic imaging for detection of aggressive human prostate cancer

摘要 前列腺癌（PCa），随着发病率的逐年上升，已成为最常见的诊断 美国男性的癌症侵袭性PCa的准确诊断对患者的生存至关重要。 经直肠超声（TRUS）引导活检，目前的标准程序，用于评估存在和 PCa的侵略性，遭受低核心产量，导致采样不足和分级不足的临床 重大肿瘤。为了填补PCa诊断中这一长期存在的严重技术空白，我们建议开发 一种新型的双模态成像平台，它集成了新兴的光声（PA）分子成像， 采用已建立的TRUS技术，用于改善临床显著PCa的检测和鉴别 肿瘤的具有绘制反映病理学的功能、化学和分子信息的独特能力， 在整个人体前列腺的条件下，在体内，非侵入性，提出的TRUS和PA（即TRUSPA） 成像可以灵敏地检测空间分布的肿瘤，更重要的是，区分侵袭性与侵袭性。 非侵袭性前列腺癌。 这项拟议的多机构研究将利用Kothapalli博士实验室在以下方面的丰富经验： 开发和翻译TRUSPA成像系统，用于人体前列腺活体成像， 博士Wang的实验室开发了PCa的新型功能成像生物标志物。核心假设是， TRUSPA能够以真实的- 用于检测和区分临床显著PCa的时间非侵入性方式。为了验证这一假设， 我们将通过与Verasonics Inc.合作开发临床级TRUSPA平台，世界领先的 研究超声系统供应商和Blatek Inc.，一家提供定制超声波的公司 换能器阵列制造。基于该平台，一组新的用于检测前列腺的成像生物标志物 肿瘤和表征PCa侵袭性将通过平行临床研究进行严格检查， 两个参与机构。为了给成功的翻译铺平道路，本研究将集中在 以下具体目标：目标1。开发并全面表征临床级TRUSPA双成像系统， PCa检测;和目标2.通过对人类受试者的研究，检查TRUSPA的临床性能， 评估一系列结构和功能成像生物标志物，以区分侵袭性和惰性PCa。 一旦所提出的PCa的TRUSPA成像的性能得到验证，这种低成本和用户友好的成像系统就可以被应用于临床。 在下一个资金周期，该技术将准备好进行适当的I/II期临床试验。TRUSPA成像， - 在体内、非侵入性地、真实的时间内检测和区分临床上显著的PCa的独特能力， 可以无缝地适应当前TRUS图像引导活检的临床程序，并具有巨大的潜力， 改变PCa管理的范式。

ABSTRACT Prostate cancer (PCa), with an annually increasing incident rate, has become the most commonly diagnosed cancer in American men. The accurate diagnosis of aggressive PCa is critical for the survival of patients. Transrectal ultrasound (TRUS) guided biopsy, the current standard procedure for evaluating the presence and aggressiveness of PCa, suffers from low core yield, leading to under-sampling and under-grading of clinically significant tumors. To fill this long-standing and serious technical gap in PCa diagnosis, we propose to develop a novel dual-modality imaging platform which integrates the emerging photoacoustic (PA) molecular imaging technique with the established TRUS for improved detection and differentiation of clinically significant PCa tumors. With the unique capability to map functional, chemical, and molecular information reflecting pathological conditions over the entire human prostate in vivo, non-invasively, the proposed TRUS and PA (namely TRUSPA) imaging can sensitively detect spatially distributed tumors and, more importantly, differentiate aggressive vs. non-aggressive PCa tumors. This proposed multi-institutional research will leverage the extensive experience of Dr. Kothapalli’s lab in developing and translating TRUSPA imaging systems for in vivo human prostate imaging, and the expertise of Dr. Wang’s lab in developing novel functional imaging biomarkers of PCa. The central hypothesis is that the TRUSPA is capable of mapping a list of functional and structural imaging biomarkers in human prostate in a real- time non-invasive manner for detecting and differentiating clinically significant PCa. To validate this hypothesis, we will develop a clinical grade TRUSPA platform through the collaborations with Verasonics Inc., a world leading provider of research ultrasound systems, and Blatek Inc., a company providing customized ultrasound transducer array fabrication. Based on this platform, a set of new imaging biomarkers for detecting prostate tumors and characterizing PCa aggressiveness will be rigorously examined via the parallel clinical studies at the two participating institutions. To pave the road toward successful translation, this research will focus on the following specific aims: Aim 1. Develop and fully characterize a clinical grade TRUSPA dual imaging system for PCa detection; and Aim 2. Via the studies on human subjects, examine the clinical performance of TRUSPA, by assessing a list of structural and functional imaging biomarkers, in distinguishing aggressive from indolent PCa. Once the performance of the proposed TRUSPA imaging of PCa is validated, this low-cost and user-friendly technology will be ready for appropriate phase I/II clinical trials in the next funding cycle. TRUSPA imaging, with the unique capability of detecting and differentiating clinically significant PCa in vivo, non-invasively, in real time, can seamlessly fit into the current clinical procedure of TRUS image-guided biopsy, and holds great potential to shift the paradigm of PCa management.