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: 9980797
• 负责人: CRISTIAN T BADEA
• 金额: $ 44.84万
• 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/9980797
• 关键词: Abscopal effect; Address; Adjuvant; American Society of Clinical Oncology; Amputation; Animals; Appearance; Archives; Autopsy; Behavior; Biological; Biological Markers; Chest; Clinical; Clinical Data; Clinical Medicine; Clinical Treatment; Clinical Trials; Code; Communities; Computer software; Correlative Study; Data; 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; Malignant Fibrous Histiocytoma; Measurement; Metastatic Neoplasm to the Lung; Methodology; Methods; Microscopy; Modeling; Monitor; Motion; Mus; Necrosis; Neoadjuvant Therapy; Neoplasm Metastasis; Oncology; Operative Surgical Procedures; Outcome; Pathology; Patients; Phase; Phase II Clinical Trials; Physiology; Preclinical Testing; 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; animal imaging; anticancer research; arm; burden of illness; cancer imaging; cancer therapy; chest computed tomography; data sharing; data warehouse; 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; microCT; mouse model; novel strategies; novel therapeutic intervention; open data; partial response; pre-clinical; pre-clinical research; preclinical imaging; preclinical study; preclinical trial; predict clinical outcome; prevent; programmed cell death protein 1; 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.

摘要 定量成像方法目前正在由定量医学委员会标准化用于临床医学。 成像生物标志物联盟（Qiba）。然而，尽管在临床前成像方面存在类似的努力， 由于临床前研究中存在高度的多样性， 成像硬件和软件。与临床（人类）成像相比，技术挑战是 对于小鼠模型定量成像的优化明显更困难。这项提案的目的是 设计、优化和应用显微磁共振成像（MRI）的临床前定量成像 和微型计算机断层扫描（CT）。具体来说，我们将应用我们的定量成像方法在一个共同的， 反映正在进行的多机构随机II期临床试验的临床试验，主要 目的探讨新辅助放疗联合帕博利珠单抗后行手术治疗的可行性。 切除术和辅助帕博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） 与单纯放疗后手术切除相比。该试验旨在评估2年和5年的 无复发生存期和总生存期。MRI用于评估放射治疗反应， 手术计划在随访期间使用胸部CT来评估远处肿瘤复发（肺转移）。 对于临床前研究，我们将使用Cre-loxP技术在小鼠后肢中产生原发性肉瘤。 小鼠我们的原位肿瘤模型在组织学外观上与人类软组织肉瘤非常相似， 基因表达和临床行为，包括肺转移发展。对于转移性肿瘤 在模型中，将切除原发性荷瘤肢体，并监测小鼠的转移。在我们的第一 具体目标，我们将开发和优化定量成像与显微MRI原发性软组织肉瘤 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。在第二个目标中，我们将实施我们优化的 在使用我们的基因工程小鼠模型的共同临床试验中， 肉瘤。我们预计，PD-1抑制剂的放疗将提高无转移生存率。的 临床前实验将提供更多的了解机制参与这些组合 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在创建一个网络- 可访问的研究资源，用于归档和传播小动物成像协议和数据。 影像学和生物学数据，包括病理学，将被稳健地整合用于相关研究。预期 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。 这一标准化将促进和指导小动物成像纳入未来的预处理和合作， 涉及癌症治疗新方法的临床试验。最终，减少了 临床前成像研究将提高建立定量相关性的价值， 病理生理学生物标志物和成像生物标志物。