Molecular guided surgery for enhanced resection of solid tumors

 描述（由申请人提供）：本提案的目标是促进候选人过渡到作为领先的学术研究人员和多学科团队成员的角色，开发基于光学荧光的技术，其目标是提高脑癌的肿瘤切除程度（EOTR）。特别是，该提案的重点是在神经外科肿瘤学的背景下推进荧光引导手术（FGS）。为此，该提案概述了一个具有强烈临床重点的指导培训计划，以补充候选人在医学和光学成像方面的熟练程度，将候选人置于关键的 达特茅斯希区柯克医学中心（DHMC）的大量NIH资助的研究人员。该计划将侧重于四个互补领域：1）提供对神经外科肿瘤学的深入了解，2）发展癌症分子生物学的专业知识，3）领导分子引导癌症手术的临床前研究，4）扩展光学工程和机器学习的技能，所有这些都将强调理解神经肿瘤学中的临床问题与解决这些问题的先进技术之间的协同作用。这些目标得到了经验丰富的导师团队的大力支持，该团队由神经外科主任罗伯茨博士领导，以及NIH资助的研究人员教授。保尔森波格和胡普斯利用达特茅斯的广泛机会，候选人将使用K99资金投入时间研究生课程在癌症生物学，医学成像和转化医学，并参加癌症研讨会，培训研讨会，并在NCI诺里斯棉花癌症中心CME认证的大圆桌会议。候选人还将参加AACR研讨会，以进一步加强对神经肿瘤学的临床理解，并为研究工作提供演讲和反馈的场所。通过本培训计划获得的坚实知识基础将应用于临床前研究项目，以开发和评价一种新的FGS方法-通过术中受体浓度成像（iRCI）进行分子引导手术（MGS）。该项目将扩展快速增长的FGS领域，应用一种新的动力学成像方法，允许术中评估肿瘤相关受体的表达，并以此指导手术切除。目的（1）将在大鼠GBM模型中开发和测试iRCI，评价MGS识别阳性组织的准确性，并与当前FGS方法相比改善EOTR。目的（2）是改进当前的FGS摄像机系统，包括动脉输入功能测量，并减少由于手术部位表面血液引起的吸收和散射伪影。目的（3）是通过染料给药和AIF表征的策略性改进，促进iRCI融入手术工作流程。该提案将扩大候选人在癌症生物学和外科肿瘤学方面的知识基础，通过广泛的培训机会和与强大的多学科导师团队的互动，为候选人提供所有必要的技能，以加速其有前途的研究生涯的轨迹。

 DESCRIPTION (provided by applicant): The goal of this proposal is to facilitate the candidate's transition to a role as a leading academic researcher and multidisciplinary team member developing optical fluorescence-based technology, with the goal of improving extent of tumor resection (EOTR) in brain cancer. In particular, a focus of this proposal is on advancing fluorescence-guided surgery (FGS) within the context of neurosurgical oncology. To this end, the proposal outlines a mentored-training program with a strong clinical emphasis to compliment the candidate's proficiency in medical and optical imaging, placing the candidate within a critical mass of NIH-funded researchers at Dartmouth Hitchcock Medical Center (DHMC). The plan will focus on four complimentary areas: 1) providing a solid understanding of neurosurgical oncology, 2) developing an expertise in cancer molecular biology, 3) leading a pre-clinical investigation of molecular-guided cancer surgery, 4) expanding skills in optical engineering and machine learning, all of which will emphasize the synergy between understanding the clinical problems in neuro-oncology and advancing technology to address these problems. These goals are strongly supported by an experienced mentor team, led by neurosurgery section-chief Dr. Roberts, alongside NIH-funded researchers Profs. Paulsen, Pogue, and Hoopes. Leveraging the extensive opportunities at Dartmouth, the candidate will use K99 funding to devote time to graduate courses in cancer biology, medical imaging, and translational medicine, and to attend cancer workshops, training seminars, and CME-accredited Grand Rounds at the NCI Norris Cotton Cancer Center. The candidate will also attend AACR workshops to further strengthen clinical understanding of neuro-oncology, and provide a venue for presentation and feedback on the research work. The firm knowledge base gained by this training plan will be applied within the context of a pre-clinical research project to develop and evaluate a novel method of FGS- molecular-guided surgery (MGS) by means of intraoperative receptor concentration imaging (iRCI). The project will extend the rapidly growing field of FGS, applying a novel kinetic imaging approach to allow intraoperative evaluation of tumor-associated receptor expression, and to use this to guide surgical resection. Aim (1) will be to develop and test iRCI in a rat model of GBM, evaluating the accuracy of MGS to identify positive tissue and to improve EOTR compared with current FGS methods. Aim (2) will be to advance the current FGS camera systems, incorporating arterial input function measurement, and reducing absorption and scatter-based artifacts due to surface blood at the surgical site. Aim (3) will be to facilitate iRCI integrationinto the surgical workflow through strategic improvements in dye administration and AIF characterization. This proposal will expand the candidate's knowledge-base in cancer biology and surgical oncology, through extensive training opportunities and interactions with a strong multi-disciplinary team of mentors, equipping the candidate with all the necessary skills to accelerate the trajectory of his promising research career.