Molecular Imaging of Fibrosis for Improved Treatment Planning of Pancreatic Ductal Adenocarcinoma

摘要胰腺导管腺癌是一种侵袭性且进展迅速的恶性肿瘤，发病时间长达五年。 尽管疗程较长且近期治疗取得进展，但总存活率仍不到9%。不幸的是， 目前可用的成像方法不能可靠地评估肿瘤对新辅助治疗的反应。这 进一步需要手术探查和重复活检以进行放化疗(CRT)后的分期。 此外，传统的解剖成像工具未能显示肿瘤的局部范围，从而导致 以次理想的肿瘤体积测量来定义放射治疗的范围。因此，非侵入性的 精确评估治疗反应和测量肿瘤大小的成像工具是非常必要的。高 纤维化程度，主要是I型胶原，已被公认为PDAC的标志。肿瘤相关 新辅助CRT治疗后纤维化进一步增加，并与患者预后改善相关 使用PDAC。在这一知识的基础上，目前的提议旨在开发一个以图像为导向的范例 使用新型I型胶原特异性PET改善PDAC的肿瘤勾画和监测治疗反应 成像探头，68Ga-CBP8。该项目如果成功，将为提供非侵入性和更多 精确的成像工具，指导临床医生优化治疗计划，降低护理成本和副作用 反复的侵入性手术，最终改善了结果。我们假设68Ga-CBP8PET 成像是一种可靠和可重复的方法，可以特异性地靶向和量化PDAC相关的纤维化。 利用动态的68Ga-CBP8PET成像和动力学模型，我们假设成像的PDAC可以是 针对静态成像进行了优化，采集时间大大缩短。在我们赠款的第二个目标中，我们假设 ~(68)Ga-CBP8 PET显像可准确定量新辅助CRT术后PDAC纤维化的增加。 因此可以作为治疗反应的替代物。最后，我们将探索68Ga-CBP8 PET是否 通过提供更准确的大体肿瘤体积测量，成像导致更精确的肿瘤勾画 与常规CT或MRI相比，当以肿瘤大小作为组织病理学的金标准时。 这项研究将由Shadi Abdar Esfahani博士进行，他是一名核医学和腹部放射学家， 麻省总医院。她将得到PET/MR的先驱Peter Caravan博士的特别指导 纤维化的分子成像，由胰腺外科医生和领先专家Kenneth Tanabe博士共同指导 胰腺癌的临床试验和生物标记物验证。建立在强大的临床经验和 在癌症模型的分子成像方面进行扎实的临床前研究，Esfahani博士的目标是成为 独立的医生-科学家，通过开发一个程序来翻译，定量的PET/MR成像的小说 癌症生物标记物，最终目标是改善临床护理和预后。这个K08奖将为她提供 通过培训和指导，她获得了独立，并申请了她的第一个R01。

Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy with a five-year overall survival of less than 9% despite long treatment course and recent therapeutic advances. Unfortunately, currently available imaging methods do not reliably evaluate the tumor response to neoadjuvant treatment. This further requires surgical exploration and repeated biopsies for post-chemoradiotherapy (CRT) staging. Additionally, the conventional anatomical imaging tools underrepresent the local extent of the tumor, which leads to suboptimal tumor volume measurement for definition of the field of radiotherapy. Therefore, a non-invasive imaging tool for precise evaluation of treatment response and tumor size measurement is of utmost need. High degree of fibrosis, mainly collagen type I, has been recognized as the hallmark of PDAC. Tumor-associated fibrosis further increases in response to neoadjuvant CRT and is correlated with improved outcome in patients with PDAC. Building on this knowledge, the current proposal aims to develop an image-guided paradigm for improving tumor delineation and monitoring treatment response in PDAC using a novel collagen I specific PET imaging probe, 68Ga-CBP8. This project, if successful, paves the way to provide a non-invasive and more accurate imaging tool to guide clinicians with optimized treatment planning, reduced cost of care and side effects of repeated invasive procedures, and ultimately improved outcome. We hypothesize that 68Ga-CBP8 PET imaging is a reliable and repeatable method that specifically targets and quantifies PDAC-associated fibrosis. Using the dynamic 68Ga-CBP8 PET imaging and kinetic modeling, we hypothesize that imaging PDAC can be optimized for static imaging with much shorter acquisition time. In our second aim of the grant, we hypothesize that 68Ga-CBP8 PET imaging precisely quantifies the increased PDAC fibrosis following neoadjuvant CRT and thereby could be used as a surrogate of treatment response. Lastly, we will explore whether 68Ga-CBP8 PET imaging results in more precise tumor delineation by providing more accurate gross tumor volume measurement compared to the conventional CT or MRI when correlated to the tumor size on histopathology gold standard. This research will be performed by Dr. Shadi Abdar Esfahani, a nuclear medicine and abdominal radiologist at Massachusetts General Hospital. She will be exceptionally mentored by Dr. Peter Caravan, a pioneer in PET/MR molecular imaging of fibrosis, and co-mentored by Dr. Kenneth Tanabe, a pancreas surgeon and leading expert in clinical trials and biomarker validation for pancreatic cancer. Building upon the strong clinical experience and solid pre-clinical research on molecular imaging of cancer models, Dr. Esfahani’s goal is to become an independent physician-scientist by developing a program for translational, quantitative PET/MR imaging of novel cancer biomarkers with the ultimate goal of improving clinical care and outcome. This K08 award will provide her with the training and mentorship needed to achieve independence and apply for her first R01.