The Duke Preclinical Research Resources for Quantitative Imaging Biomarkers

摘要 定量成像方法目前正被用于临床医学的标准化 成像生物标记物联盟(QIBA)。然而，临床前成像的类似努力并不存在，尽管 标准化的需求更加迫切，因为临床前存在着高度的多样性 成像硬件和软件。与临床(人体)成像相比，技术挑战是 明显增加了优化小鼠模型定量成像的难度。这项提议的目标是 临床前微磁共振成像定量成像的设计、优化和应用 和微型计算机断层扫描(CT)。具体地说，我们将把我们的定量成像方法应用于联合- 反映正在进行的、多机构的、随机的II期临床试验的临床试验，该试验具有主要的 摘要目的探讨新辅助放射治疗联合培溴利珠单抗在手术治疗中的作用。 切除和辅助培溴利珠单抗可提高高危软组织患者的无病生存率 四肢肉瘤(未分化多形性肉瘤或去分化/多形性脂肪肉瘤) 与单纯放射治疗后手术切除相比。该试验旨在评估为期2年和5年的 无复发生存期和总生存期。磁共振成像用于评估放射治疗的反应和 为手术做计划。在随访期间使用胸部CT来评估远处肿瘤复发(肺转移)。 在临床前研究中，我们将使用Cre-loxP技术在小鼠的后肢产生原发性肉瘤 老鼠。我们的本土肿瘤模型在组织学形态上非常接近人类软组织肉瘤， 基因表达和临床行为，包括肺转移的发展。对于转移性肿瘤 模型建立后，将截断主要的荷瘤肢体，并监测小鼠的转移情况。在我们的第一次 明确目标，我们将开发和优化原发性软组织肉瘤的显微MRI定量成像 肿瘤和肺转移的微型CT检查。我们将遵循旗吧中提出的类似方法 框架，但适用于小动物成像。在第二个目标中，我们将实现我们的优化 使用我们的基因工程小鼠模型进行的联合临床试验中的定量成像方法 肉瘤。我们预计，使用PD-1抑制剂的放射治疗将提高无转移生存率。这个 临床前实验将更好地理解这些联合作用的机制。 并将向未来的临床试验提供信息。最后，最后一个具体目标将集中在创建一个网络-- 可访问的研究资源，用于存档和传播小动物成像方案和数据。 影像和生物数据，包括病理学，将被强有力地整合起来，用于相关研究。预期中的 该项目的成果是癌症研究的微型核磁共振和微型CT临床前成像的标准化。 这一标准化将促进和指导将小动物成像纳入未来的预成像和联合成像。 涉及癌症治疗的新治疗方法的临床试验。归根结底，减少 临床前影像研究将提高定量相关性的价值 病理生理生物标记物和影像生物标记物。

Abstract Quantitative imaging approaches are currently being standardized for clinical medicine by the Quantitative Imaging Biomarkers Alliance (QIBA). However, similar efforts for preclinical imaging do not exist although the need for standardization is even more pressing because of the high degree of diversity that exists in preclinical imaging hardware and software. Compared to clinical (human) imaging, the technical challenges are significantly more difficult for the optimization of mouse model quantitative imaging. The goal of this proposal is to design, optimize and apply preclinical quantitative imaging with micro-magnetic resonance imaging (MRI) and micro- computed tomography (CT). Specifically, we will apply our quantitative imaging methods in a co- clinical trial which mirrors an on-going, multi-institutional, randomized phase II clinical trial that has a primary objective to investigate whether neoadjuvant radiotherapy combined with pembrolizumab followed by surgical resection and adjuvant pembrolizumab improves disease-free survival for patients with high-risk soft-tissue sarcoma of the extremity (undifferentiated pleomorphic sarcoma or dedifferentiated/pleomorphic liposarcoma) compared to radiotherapy alone followed by surgical resection. The trial aims to evaluate the 2- and 5-year recurrence-free survival and overall survival. MRI is used to assess the radiation treatment response and to plan for surgery. Chest CT is used during follow up to evaluate for distant tumor recurrence (lung metastases). For preclinical studies, we will use the Cre-loxP technology to generate primary sarcomas in the hind limb of mice. Our autochthonous tumor models closely mimic human soft tissue sarcomas in histologic appearance, gene expression, and clinical behavior, including lung metastasis development. For the metastatic tumor model, the primary tumor-bearing limb will be amputated and mice will be monitored for metastases. In our first specific aim, we will develop and optimize quantitative imaging with micro-MRI for primary soft tissue sarcoma tumors and micro-CT for lung metastases. We will follow similar methodologies proposed in the QIBA framework but adapted for small animal imaging. During the second aim, we will implement our optimized quantitative imaging methods in the co-clinical trial using our genetically engineered mouse models of sarcoma. We anticipate that radiotherapy with PD-1 inhibitors will improve metastasis-free survival. The preclinical experiments will provide greater understanding of mechanisms involved in these combined therapies and will inform future clinical trials. Finally, the last specific aim will focus on creating a web- accessible research resource for archiving and disseminating small animal imaging protocols and data. Imaging and biologic data, including pathology, will be robustly integrated for correlative studies. The expected outcome of this project is the standardization of micro-MRI and micro-CT preclinical imaging for cancer studies. This standardization will facilitate and guide the incorporation of small animal imaging into future pre- and co- clinical trials involving new therapeutic approaches to cancer treatment. Ultimately, reduced variability in preclinical imaging studies will improve the value of quantitative correlations established between pathophysiological biomarkers and imaging biomarkers.