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.

项目摘要 卵巢癌是一个沉默的杀手，击中很少（如果有的话）。当一个女人知道她有它时， 癌症通常是晚期的，外观严峻。但是，如果提早发现上皮卵巢癌 患者的预后非常好。开发非侵入性和高度特定的血液测试，以预先 因此，症状筛查和卵巢癌的早期检测至关重要。这尤其重要 由于进行活检是困难，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，缺乏早期检测该沉默杀手的必要敏感性和特异性。基本 挑战是从发育肿瘤释放的循环生物分子的极低浓度 在临床前阶段，可能比其临床可检测水平低10,000倍。因此，有一个 迫切需要发现新颖的生物标志物，采用新策略并开发强大的技术来推动 癌症诊断的进步，特别是在卵巢癌等疾病中。我们集中精力 在小细胞外蔬菜（SEV）上，源自内溶性的主要大小外泌体 途径，在细胞通信，免疫响应和癌症进展中起着重要作用 选择性生物分子的选择性曲目。大多数SEV/外泌体释放显着增加 肿瘤细胞，包括卵巢癌，并在肿瘤发育的所有阶段不断发生。瘤- 衍生的SEV积聚在人血和恶性积液中。这些蔬菜携带丰富的子集 反映原始肿瘤细胞的生物分子，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的内在检测 早期恶性转化期间的低级血清标记。那，构成释放和丰富 SEV中的某些肿瘤标记为早期癌症诊断提供了独特的机会。我们 假设循环中的SEV，非常类似于循环的肿瘤细胞，但由于其主动释放而更稳固 人身烟道中令人难以置信的稳定性，代表了早期发现外二元标记物的更大来源 检测，可能仍局限于输卵管。此外，SEV可以用作“液体活检” 评估癌症患者实时的益处和治疗反应。我们的创新应用程序合并EV 使用纳米材料/微流体技术的生物学，开发出高级微流体平台以捕获和 从循环中检测具有高特异性和灵敏度的卵巢癌衍生的SEV。这种方法会 综合验证的输卵管和卵巢癌相关的外蛋白生物标志物（SA1）将是 应用于第二代纳米工程EV分析芯片（SA2）。这些研究将随后 使用从不对称妇女那里收集的纵向样本的临床验证，后来发展上皮 卵巢癌（SA3）。我们的最终目标是开发可靠的基于血液的测定法 与当前筛查方法的结合将降低卵巢癌的死亡率。

项目成果

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

• DOI: 10.1016/j.amjcard.2022.04.031
• 发表时间: 2022-08-01
• 期刊: AMERICAN JOURNAL OF CARDIOLOGY
• 影响因子: 2.8
• 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.

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

• DOI: 10.3389/frai.2023.1260361
• 发表时间: 2023
• 期刊: FRONTIERS IN ARTIFICIAL INTELLIGENCE
• 影响因子: 4
• 作者: Chang, Hung-Ching;Gitau, Antony M.;Kothapalli, Siri;Welch, Danny R.;Sardiu, Mihaela E.;Mccoy, Matthew D.
• 通讯作者: Mccoy, Matthew D.

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

• DOI: 10.1188/22.cjon.533-542
• 发表时间: 2022-09-15
• 期刊: Clinical journal of oncology nursing
• 影响因子: 1.1

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

• DOI: 10.1016/j.jcte.2023.100321
• 发表时间: 2023-09
• 期刊: JOURNAL OF CLINICAL AND TRANSLATIONAL ENDOCRINOLOGY
• 影响因子: 3
• 作者: Gopinath, Chaitra;Crow, Hanna;Panthi, Sujata;Bantis, Leonidas;Burman, Kenneth D.;Choudhary, Chitra
• 通讯作者: Choudhary, Chitra