Developing multiplexed microenvironmental sensors for precision diagnostics of cancer metastasis

开发用于癌症转移精确诊断的多重微环境传感器

• 批准号: 10063499
• 负责人: Liangliang Hao
• 金额: $ 10.13万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063499
• 关键词: Address; Analytical Chemistry; Anatomy; Architecture; Area; Bar Codes; Benchmarking; Biological; Biological Assay; Biological Markers; Biology; Biosensor; Blood; CRISPR/Cas technology; Cancer Etiology; Cancer Model; Career Mobility; Cause of Death; Characteristics; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Colorectal Cancer; Complement; Complex; DNA; Dependence; Detection; Development; Diagnosis; Diagnostic; Diagnostic Sensitivity; Diffuse; Disease; Disease stratification; Early Diagnosis; Emission-Computed Tomography; Engineering; Enzymes; Evaluation; Excision; Exhibits; Extracellular Matrix; Fostering; Future; Generations; Genetic; Goals; Homing; Human; Image; Imaging Device; Imaging Techniques; Immune; Immunoglobulin Fragments; In Vitro; Injectable; Intervention; Invaded; Investigation; Lesion; Libraries; Light; Malignant Neoplasms; Medical; Medical Imaging; Mentors; Modality; Molecular; Molecular Profiling; Monitor; Mutation; Neoplasm Metastasis; Non-Invasive Cancer Detection; Nucleic Acids; Oligonucleotides; Oncology; Operative Surgical Procedures; Paper; Patients; Peptide Hydrolases; Peptides; Positron-Emission Tomography; Precision therapeutics; Primary Neoplasm; Property; Proteomics; Radiation; Recombinants; Reporter; Reporting; Research; Resources; Sampling; Sensitivity and Specificity; Signal Transduction; Site; Specificity; Survival Rate; Testing; Therapeutic; Time; Training; United States National Institutes of Health; Urine; Validation; Visualization; X-Ray Computed Tomography; base; cancer cell; cancer diagnosis; cancer type; cell motility; colorectal cancer metastasis; colorectal cancer screening; design; detection sensitivity; diagnostic biomarker; diagnostic platform; disease classification; efficacy validation; experience; improved; in vivo; innovation; interdisciplinary approach; metastatic colorectal; molecular imaging; mortality; nanobodies; nanosensors; novel; novel strategies; novel therapeutics; organoid transplantation; personalized approach; personalized diagnostics; point-of-care diagnostics; portability; pre-clinical; precision medicine; programs; response; scaffold; sensor; technology development; theranostics; therapy outcome; tool; trafficking; transcriptomics; transplant model; treatment response; treatment strategy; tumor; tumor heterogeneity; tumor microenvironment; urinary

Summary More than 90% of all cancer-related deaths are caused by metastasis, the spread of cancer from its origin. By the time most cancer metastases become clinically visible, the disease has progressed too far to benefit from early-stage interventions such as surgery or radiation. Thus, new approaches accessing specific diagnostic biomarkers are highly desired to improve therapeutic outcomes. Microenvironmental signatures such as extracellular matrix (ECM) alterations, stromal composition, or immune components exhibit critical determinants of metastatic dissemination broadly across cancers. Herein, the main goal of this proposal is to converge the disease hall markers and rational design of biomolecular engineering to develop multidisciplinary approaches towards precision diagnostics of cancer metastasis. As metastases start to invade, they alter the extracellular matrix through aberrant proteolytic activities that could be leveraged as biomarkers. The applicant set out to systematically identify proteases expressed in metastatic colorectal cancer (CRC) by transcriptomic and proteomic analysis. To improve the detection sensitivity, it is proposed to integrate the proteolytic activity to formulate a library of enzyme activated sensors by reengineering the ECM targeting nanobody with extraordinarily tumor targeting efficacy for maximal on-target signal generation (Aim 1). To optimize the detection specificity, the multiplexity of these activity-based sensors will be extensively expanded for disease classification using CRISPR-Cas-based nucleic acid barcode readout. Preliminary investigation into the in vivo DNA barcodes revealed that they could be detected noninvasively as a urinary reporter, but could also enable portable detection on paper (Aim 2). Beyond initial diagnosis, disease stratification and treatment monitoring are critical to establishing a robust therapy. The novel sensors will thus be evaluated for noninvasive tumor monitoring and imaging in disease recapitulating metastatic CRC models (Aim 3). Successful completion of these three aims would offer a tumoral activation responsive, genetically encoded tracking (TARGET) platform can 1) unveil new biology at the metastasis-specific tumor microenvironment, 2) provide a completely noninvasive way to track tumor metastasis, and 3) offer a pipeline for validating novel therapies, which are currently unachievable by single modality agents. This project requires innovative integration across several fields. The candidate has assembled an exceptional team to help her achieve the goals of technology development and career transition, including her mentor Dr. Sangeeta Bhatia (MIT, medical engineering) and Drs. Tyler Jacks (MIT, tumor genetics), Dr. Richard Hynes (MIT, extracellular matrix), Dr. Frank Gertler (MIT, cell motility) and Dr. Shawn Chen (NIH, theranostics) on the mentoring committee. This training period will allow the candidate to gain experience in tumor microenvironment network, pre-clinical cancer models and analytical chemistry. In the future, the principles of this modular platform could apply to other disease areas. The research program here aligns well with the candidate’s long-term goal to develop multi-scale engineered tools in the context of cancer.

概括 所有与癌症相关的死亡中有90％以上是由转移引起的，这是癌症源于其起源的传播。 到大多数癌症转移在临床上可见时，该疾病已经进展得太远，无法从中受益 早期干预措施，例如手术或辐射。那是访问特定诊断的新方法 高度希望生物标志物改善治疗结果。微环境签名，例如 细胞外基质（ECM）改变，基质组成或免疫成分暴露于关键决定剂 跨癌症广泛的转移性传播。在此，该提议的主要目标是融合 疾病大厅标记和生物分子工程的合理设计，以开发多学科方法 迈向癌症转移的精确诊断。随着转移开始入侵，它们会改变细胞外 通过异常蛋白水解活性的基质可以用作生物标志物。申请人列出 有系统地识别通过转录组和转移性结直肠癌（CRC）表达的蛋白酶 蛋白质组学分析。为了提高检测敏感性，提议将蛋白水解活性整合到 通过重新设计靶向纳米机构的ECM来制定酶激活传感器的库 最大目标信号产生最大的肿瘤靶向效率（AIM 1）。优化检测 特异性，这些基于活动的传感器的多重性将被广泛扩展以进行疾病分类 使用基于CRISPR-CAS的核酸条形码读数。对体内DNA条形码的初步研究 揭示它们可以作为尿道记者无创，但也可以启用便携式检测 在纸上（目标2）。除了初始诊断之外，疾病分层和治疗监测至关重要 建立强大的疗法。因此，将评估新型传感器的无创肿瘤监测和 在疾病中概括转移性CRC模型的成像（AIM 3）。这三个目标成功完成 将提供肿瘤激活响应，遗传编码的跟踪（目标）平台1）揭开新的 在转移特异性肿瘤微环境中的生物学，2）提供了一种完全无创的方法 肿瘤转移和3）提供了验证新疗法的管道，目前无法实现。 单形态剂。该项目需要在几个领域进行创新整合。候选人有 组建了一个杰出的团队，以帮助她实现技术发展和职业过渡的目标， 包括她的心理Sangeeta Bhatia博士（麻省理工学院，医学工程）和Drs。泰勒·杰克斯（MIT，肿瘤遗传学）， 理查德·海恩斯（MIT，细胞外矩阵），弗兰克·格特勒博士（麻省理工学院，细胞运动）和肖恩·陈（Shawn Chen）（NIH，NIH， 心理委员会的疗法。这个培训期将使候选人能够获得 肿瘤微环境网络，临床前癌症模型和分析化学。将来，原理 这个模块化平台可能适用于其他疾病领域。这里的研究计划与 候选人在癌症中开发多规模工程工具的长期目标。