The Duke Preclinical Research Resources for Quantitative Imaging Biomarkers

杜克大学定量成像生物标志物临床前研究资源

• 批准号: 9387149
• 负责人: CRISTIAN T BADEA
• 金额: $ 59.27万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387149
• 关键词: Address; Adjuvant; American Society of Clinical Oncology; Amputation; Animals; Appearance; Archives; Autopsy; Behavior; Biological Markers; Cessation of life; Chest; Clinical; Clinical Data; Clinical Medicine; Clinical Treatment; Clinical Trials; Code; Communities; Computer software; Correlative Study; Data; Data Science; Data Set; Databases; Deposition; Development; Disease; Disease-Free Survival; Distant; Documentation; Effectiveness; Excision; Future; Gene Expression; Genetic Engineering; Genetically Engineered Mouse; Goals; Histologic; Human; Image; Immune checkpoint inhibitor; Immune response; Immune system; Immunotherapy; Limb structure; Magnetic Resonance Imaging; Measurement; Metastatic Neoplasm to the Lung; Methodology; Methods; Microscopy; Modeling; Monitor; Motion; Mus; Necrosis; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pathology; Patients; Phase; Phase II Clinical Trials; Physiology; Primary Neoplasm; Progression-Free Survivals; Protocols documentation; Publications; Radiation therapy; Randomized; Reader; Recurrence; Research; Research Proposals; Resolution; Resources; Science; Soft tissue sarcoma; Standardization; Technology; Testing; Treatment outcome; Undifferentiated; X-Ray Computed Tomography; animal imaging; anticancer research; arm; burden of illness; cancer imaging; cancer therapy; chest computed tomography; data sharing; design; experimental study; follow-up; high risk; human imaging; imaging approach; imaging biomarker; imaging modality; imaging study; improved; in vivo; in vivo imaging; inhibitor/antagonist; liposarcoma; mouse model; novel strategies; novel therapeutic intervention; oncology; open data; partial response; pre-clinical; pre-clinical research; pre-clinical trial; preclinical study; predict clinical outcome; prevent; public health relevance; quantitative imaging; reconstruction; repository; response; sarcoma; treatment response; tumor; web-accessible

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.

抽象的 目前，定量成像方法正在通过定量成像方法标准化为临床医学。 成像生物标志物联盟（QIBA）。然而，尽管临床前成像方面的类似努力并不存在 由于临床前研究存在高度多样性，对标准化的需求更加迫切 成像硬件和软件。与临床（人类）成像相比，技术挑战是 小鼠模型定量成像的优化难度明显加大。该提案的目标是 通过微磁共振成像 (MRI) 设计、优化和应用临床前定量成像 和显微计算机断层扫描 (CT)。具体来说，我们将在合作中应用我们的定量成像方法 临床试验，反映正在进行的、多机构、随机 II 期临床试验，该试验具有主要 目的探讨新辅助放疗联合派姆单抗（pembrolizumab）随后进行手术是否有效 切除和辅助帕博利珠单抗可改善高危软组织患者的无病生存期 四肢肉瘤（未分化多形性肉瘤或去分化/多形性脂肪肉瘤） 与单独放疗然后手术切除相比。该试验旨在评估 2 年和 5 年 无复发生存期和总生存期。 MRI 用于评估放射治疗反应并 计划手术。胸部 CT 用于随访期间评估远处肿瘤复发（肺转移）。 对于临床前研究，我们将使用 Cre-loxP 技术在后肢生成原发性肉瘤 老鼠。我们的本土肿瘤模型在组织学外观上非常模仿人类软组织肉瘤， 基因表达和临床行为，包括肺转移的发展。对于转移性肿瘤 模型中，原发肿瘤肢体将被截肢，并监测小鼠的转移情况。在我们的第一个 针对特定目标，我们将开发和优化原发性软组织肉瘤的显微 MRI 定量成像 肿瘤和肺转移的显微 CT。我们将遵循 QIBA 中提出的类似方法 框架但适用于小动物成像。在第二个目标期间，我们将实施我们的优化 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 PD-1 抑制剂放疗将改善无转移生存率。这 临床前实验将更好地理解这些组合所涉及的机制 疗法并将为未来的临床试验提供信息。最后，最后一个具体目标将集中于创建一个网络- 用于存档和传播小动物成像协议和数据的可用研究资源。 影像和生物数据（包括病理学）将被强有力地整合以进行相关研究。预期的 该项目的成果是用于癌症研究的微型 MRI 和微型 CT 临床前成像的标准化。 这种标准化将促进和指导将小动物成像纳入未来的预检和联合检测中。 涉及癌症治疗新方法的临床试验。最终，减少了变化 临床前成像研究将提高之间建立的定量相关性的价值 病理生理学生物标志物和成像生物标志物。