Extracellular Vesicle Proteomic Fingerprinting of Ovarian Cancer for Early Detection with a Nanoengineered Microsystem

卵巢癌细胞外囊泡蛋白质组指纹图谱用于纳米工程微系统的早期检测

• 批准号: 10737826
• 负责人: ANDREW K. GODWIN
• 金额: $ 15.79万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737826
• 关键词: 3-Dimensional; Advanced Malignant Neoplasm; Advisory Committees; Area; BRCA mutations; Benign; Biological Assay; Biological Markers; Biology; Biopsy; Blood; Blood capillaries; Blood specimen; Body Fluids; CA-125 Antigen; Cancer Control; Cancer Detection; Cancer Diagnostics; Cancer Patient; Cancer cell line; Carcinoma in Situ; Cell Line; Circulation; Clinical; Clinical Sensitivity; Colon Carcinoma; Communication; Companions; Detection; Development; Diagnosis; Diagnostic Sensitivity; Disease; Drops; Early Diagnosis; Engineering; Epithelial ovarian cancer; Excision; Fingerprint; General Population; Generations; Goals; Human; Immune response; Immunoassay; Immunoprecipitation; Intervention; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of ovary; Mammalian Oviducts; Mass Spectrum Analysis; Messenger RNA; Methods; MicroRNAs; Microfluidics; Nanochip Analytical Device; Neoplasm Circulating Cells; Operative Surgical Procedures; Outcome; Ovarian; Ovary; Pathway interactions; Patients; Pattern; Plasma; Play; Population Control; Printing; Proteins; Proteomics; Public Health; Reporting; Reproducibility; Risk; Role; Sampling; Screening for Ovarian Cancer; Screening for cancer; Sensitivity and Specificity; Serous; Serum Markers; Signaling Protein; Solid Neoplasm; Source; Specificity; Specimen; Symptoms; Technology; Testing; Time; Tissues; Training; Tumor Antigens; Tumor Markers; Tumor stage; Tumor-Derived; Ultrasonography; Untranslated RNA; Vagina; Validation; Vesicle; Woman; biomarker panel; cancer diagnosis; candidate marker; candidate validation; clinical diagnosis; clinical translation; cost; curative treatments; detection assay; diagnostic platform; disorder risk; early detection biomarkers; effusion; exosome; extracellular vesicles; high risk population; imaging modality; innovation; liquid biopsy; malignant breast neoplasm; microchip; microfluidic technology; microsystems; mortality; mutation carrier; nano; nanoengineering; nanomaterials; nanopattern; neoplastic cell; novel; novel marker; patient prognosis; pre-clinical; presymptomatic testing; prevention service; protein biomarkers; protein profiling; routine screening; screening; self assembly; tool; treatment response; tumor; tumor progression

PROJECT SUMMARY Ovarian cancer is a silent killer that strikes with few, if any, symptoms. By the time a woman knows she has it, the cancer is often advanced and the outlook grim. However, if epithelial ovarian cancer is caught early the prognosis for the patient is excellent. Developing non-invasive and highly specific blood-based tests for pre- symptomatic screening and early detection of ovarian cancer is therefore crucial. This is especially essential since obtaining a biopsy is difficult, costly, and sometimes not even an option. In addition, most blood biomarkers to date lack the necessary sensitivity and specificity for early detection of this silent killer. A fundamental challenge is the extremely low concentrations of circulating biomolecules released from the developing tumors at pre-clinical stages which can be 10,000-fold lower than their clinically detectable levels. Therefore, there is a pressing need to uncover novel biomarkers, apply new strategies, and develop robust technologies to propel the advancement of cancer diagnostics, especially in a disease such as ovarian cancer. We have focused our efforts on small extracellular vesicles (sEVs), primarily small and large exosomes derived from the endolysosomal pathway, which play important roles in cellular communication, immune response, and cancer progression via transfer of a selective repertoire of biomolecules. sEVs/exosome release is significantly increased in most neoplastic cells, including ovarian cancer and occurs continuously at all stages of tumor development. Tumor- derived sEVs accumulate in human blood and malignant effusions. These vesicles carry enriched subsets of biomolecules mirroring the tumor cells of origin, such as signaling proteins, tumor antigens, and functional RNAs (mRNA and miRNAs), which offer a new strategy to surmount the challenge in reliable detection of intrinsically low-level serum markers during early malignant transformation. Thus, the constitutive release and enrichment of certain tumor markers within sEVs present distinctive opportunities for early cancer diagnosis. We hypothesize that circulating sEVs, much akin to circulating tumor cells but more robust due to their active release and incredible stability in bodily fluids, represent a greater source for the discovery of exo-biomarkers for early detection, potentially while still confined to the fallopian tube. In addition, sEVs can serve as a 'liquid biopsy’ to assess benefits and treatment responses in real time in cancer patients. Our innovative application merges EV biology with nano-material/microfluidic technology to develop an advanced microfluidic platform to capture and detect ovarian cancer-derived sEVs with high specificity and sensitivity from the circulation. This approach will integrate validated fallopian tube and ovarian cancer associated exo-protein biomarkers (SA1), which will be applied to a second-generation nano-engineered EV analysis chip (SA2). These studies will be followed by clinical validation using longitudinal samples collected from asymptomatic women who later develop epithelial ovarian cancer (SA3). Our ultimate goal is to develop a reliable blood-based assay that, when used in conjunction with current screening approaches will decrease the mortality from ovarian cancer.

项目概要 卵巢癌是一种无声杀手，当女性知道自己患有卵巢癌时，几乎没有任何症状。 癌症通常已是晚期，前景严峻。然而，如果上皮性卵巢癌及早发现，则可能会带来严重的后果。 开发非侵入性和高度特异性的基于血液的预检测，患者的预后非常好。 因此，卵巢癌的症状筛查和早期发现尤为重要。 因为获得活检是困难的、昂贵的，有时甚至不是一种选择。此外，大多数血液生物标志物。 迄今为止，缺乏必要的敏感性和特异性来早期发现这个无声杀手。 挑战是从发育中的肿瘤释放的循环生物分子浓度极低 在临床前阶段，其含量可能比临床可检测水平低 10,000 倍。 迫切需要发现新的生物标志物、应用新的策略并开发强大的技术来推动 我们致力于癌症诊断的进步，特别是在卵巢癌等疾病方面。 小细胞外囊泡（sEV），主要是源自内溶酶体的小外泌体和大外泌体 途径，在细胞通讯、免疫反应和癌症进展中发挥重要作用 在大多数情况下，选择性生物分子库的转移/外泌体释放显着增加。 肿瘤细胞，包括卵巢癌，在肿瘤发展的各个阶段持续发生。 衍生的 sEV 在人类血液和恶性积液中积累，这些囊泡携带丰富的亚群。 反映肿瘤细胞来源的生物分子，例如信号蛋白、肿瘤抗原和功能性 RNA （mRNA 和 miRNA），它提供了一种新的策略来克服可靠检测本质上的挑战 早期恶性转化期间血清标志物水平较低，因此，组成型释放和富集。 sEV 中某些肿瘤标志物的检测为早期癌症诊断提供了独特的机会。 循环 sEV，与循环肿瘤细胞非常相似，但由于其主动释放而更加强大 以及在体液中令人难以置信的稳定性，为早期发现外生物标志物提供了更大的来源 检测，但可能仍局限于输卵管此外，sEV 可以作为“液体活检”。 我们的创新应用程序融合了 EV，实时评估癌症患者的获益和治疗反应。 生物学与纳米材料/微流体技术开发先进的微流体平台来捕获和 这种方法能够以高特异性和敏感性从循环中检测卵巢癌衍生的 sEV。 整合经过验证的输卵管和卵巢癌相关外切蛋白生物标志物 (SA1)，这将是 这些研究将应用于第二代纳米工程电动汽车分析芯片（SA2）。 使用从后来发展为上皮细胞的无症状女性收集的纵向样本进行临床验证 我们的最终目标是开发一种可靠的基于血液的检测方法，用于卵巢癌（SA3）。 结合当前的筛查方法将降低卵巢癌的死亡率。

项目成果

Ovarian Cancer Symptom Clusters: Use of the NIH Symptom Science Model for Precision in Symptom Recognition and Management.

卵巢癌症状群：使用 NIH 症状科学模型精确识别和管理症状。

• 发表时间: 2022-09-15
• 作者: Mahoney, Diane E;Pierce, Janet D
• 通讯作者: Pierce, Janet D

Effects of Ubiquinol and/or D-ribose in Patients With Heart Failure With Preserved Ejection Fraction.

泛醇和/或 D-核糖对射血分数保留的心力衰竭患者的影响。

• 发表时间: 2022-08-01
• 作者: Pierce, Janet D;Shen, Qiuhua;Mahoney, Diane E;Rahman, Faith;Krueger, Kathryn J;Diaz, Francisco J;Clark, Lauren;Smith, Carol;Vacek, James;Hiebert, John B
• 通讯作者: Hiebert, John B

Characteristics, staging and outcomes of differentiated thyroid cancer in patients with and without Graves' disease.

患有和不患有格雷夫斯病的患者分化型甲状腺癌的特征、分期和结果。

• 发表时间: 2023-09
• 作者: Gopinath, Chaitra;Crow, Hanna;Panthi, Sujata;Bantis, Leonidas;Burman, Kenneth D;Choudhary, Chitra
• 通讯作者: Choudhary, Chitra

Understanding the need for digital twins' data in patient advocacy and forecasting oncology.

了解在患者宣传和预测肿瘤学方面对数字孪生数据的需求。

• 发表时间: 2023
• 作者: Chang, Hung;Gitau, Antony M;Kothapalli, Siri;Welch, Danny R;Sardiu, Mihaela E;McCoy, Matthew D
• 通讯作者: McCoy, Matthew D