SESORRS endoscopy for the staging and evaluation of colorectal cancer

项目总结/摘要： 结直肠癌（CRC）是世界范围内第三大常见癌症，也是导致死亡的主要原因。程度 大肠癌侵袭大肠壁的可能性与患者预后有关。白色光内镜（WLE） 用于评价结肠内感兴趣的病变，然而WLE仅提供形态学信息， 通常不能有效地评估所需的切除边缘或肿瘤侵袭的程度。存在显著 需要开发一种内窥镜方法来应对这些挑战。我们相信这是可以实现的 结合使用空间偏移拉曼光谱（SORS）和表面增强共振拉曼 散射（SERRS）造影剂（CA）。这两种方法的组合称为表面 增强空间偏移共振拉曼光谱（SESORRS）。在拟定的临床前研究中，我将 检验SESORRS内窥镜检查可以改善现有的检测、分期和 手术切除CRC。在K99指导阶段，我将构建SORS并验证其效率 使用离体模的内窥镜（SA1.1，SA1.2）。使用CRC的Apcfl/+和Apcfl/+; KrasG 12 D/+小鼠模型， 我们将评估SESORRS内窥镜在体内检测和分期结直肠癌的效率。结果将 与MRI、PET和离体组织学相关（SA2.1）。的生物分布和药代动力学特征 将使用PET成像评价放射性标记的SERRS CA（SA2.2）。作为独立调查员，我会 确定CRC SORS内镜成像所需的SERRS CA的最佳剂量（SA2.3）。在SA 3 I中 将确定和验证使用分子靶向SERRS CA相对于非靶向SERRS的优势 CA，以及SESORRS内窥镜辅助手术切除感兴趣病变的能力， 检测切除床表面和下方的残留肿瘤细胞。如果成功，SESORRS 内镜检查在结直肠癌的筛查、诊断和治疗中非常有用。这个项目将使我们 预测临床SESORRS内窥镜检查的潜在成功，并增加实现 最终的临床翻译。我在SERRS、SORS和SESORRS成像方面拥有一套独特的专业知识， 我相信我是非常合格的领导，并进行，在达纳法伯癌症研究所提出的项目。 我还确定了以下需要额外培训的关键领域，以支持我过渡到 独立性：（1）CRC的小鼠模型;（2）了解CRC的癌症生物学和 基因突变对CRC侵袭的影响;（3）放射化学和PET成像;（4）临床要求 翻译.我精心挑选并组建了一个世界级的导师和顾问委员会 包括我的主要导师凯文·海吉斯博士，以及康纳·L。埃文斯和诺曼·西冈博士 担任共同导师。我的导师完全支持我的研究和职业目标。我致力于此 我很高兴获得这个奖项，并坚信它将帮助我获得必要的培训，使我的长期职业生涯 目标是成为分子成像领域的既定研究者。

PROJECT SUMMARY/ABSTRACT: Colorectal cancer (CRC) is the third most common cancer and a leading cause of death worldwide. The degree of CRC invasion into the large intestinal wall is associated with patient prognosis. White light endoscopy (WLE) is used to evaluate lesions of interest within the colon, however WLE provides only morphological information, often failing to efficiently evaluate the required resection margin or extent of tumor invasion. There is a significant need to develop an endoscopic approach that can address these challenges. We believe this could be achieved using spatially offset Raman spectroscopy (SORS) in combination with surface enhanced resonance Raman scattering (SERRS) contrast agents (CAs). The combination of the two approaches is referred to as surface enhanced spatially offset resonance Raman spectroscopy (SESORRS). In the proposed preclinical study, I will test the hypothesis that SESORRS endoscopy could improve existing practices for the detection, staging and surgical resection of CRC. During the K99 mentored phase, I will build and validate the efficiency of a SORS endoscope using ex vivo phantoms (SA1.1, SA1.2). Using Apcfl/+ and Apcfl/+;KrasG12D/+ mouse models of CRC, we will evaluate the efficiency of SESORRS endoscopy to detect and stage CRC in vivo. Results will be correlated with MRI, PET, and ex vivo histology (SA2.1). The biodistribution and pharmacokinetic profiles of radiolabeled SERRS CAs will be evaluated using PET imaging (SA2.2). As an independent investigator, I will determine the optimal dose of SERRS CAs required for SORS endoscopic imaging of CRC (SA2.3). In SA3 I will determine and validate the advantage of using molecularly targeted-SERRS CAs over non-targeted SERRS CAs, together with the ability of SESORRS endoscopy to assist in the surgical resection of lesions of interest by detecting residual tumor cells on the surface, and beneath, the resection bed. If successful, SESORRS endoscopy could be very useful in the screening, diagnosis, and treatment of CRC. This project will enable us to predict the potential success of clinical SESORRS endoscopy and increase the likelihood of achieving eventual clinical translation. I have a unique set of expertise in SERRS, SORS and SESORRS imaging and believe I am highly qualified to lead, and conduct, the proposed project here at the Dana-Farber Cancer Institute. I also have identified the following key areas which require additional training in order to support my transition to independence: (1) mouse models of CRC; (2) understanding the cancer biology of CRC and the influence of genetic mutations on CRC invasion; (3) radiochemistry and PET imaging and; (4) requirements for clinical translation. I have deliberately chosen and carefully assembled a world-class committee of mentors and advisors including my primary mentor Dr. Kevin Haigis, as well as Dr. Conor L. Evans and Dr. Norman Nishioka who will serve as co-mentors. My mentors are in full support of my research and career goals. I am committed to this award and strongly believe that it will help me gain the necessary training required to enable my long-term career goal of being an established investigator in the field of molecular imaging.