Validating Urine Derived Cancer Cells (UDCC) -- Non-Invasive and Living Liquid Biopsies -- in Bladder Cancer Clinics

在膀胱癌诊所中验证尿液衍生癌细胞 (UDCC)——非侵入性活体液体活检

• 批准号: 10605346
• 负责人: Xuefeng Liu
• 金额: $ 38.39万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605346
• 关键词: Address; Adjuvant Chemotherapy; Biological Markers; Bladder; Bladder Neoplasm; Cancer Center; Cancer Detection; Cancer Patient; Cell Culture Techniques; Cells; Clinic; Clinical; Clinical Management; Clinical Treatment; Cystoscopy; Cytology; Data; Detection; Development; Diagnosis; Early Diagnosis; European; Exhibits; Funding; Goals; Health Personnel; Human; Human body; Immune; Immunotherapy; In Vitro; In complete remission; Intravesical Instillation; Laboratories; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical; Messenger RNA; Methods; MicroRNAs; Modeling; Monitor; Mutation; National Center for Advancing Translational Sciences; Nature; Neoadjuvant Therapy; Neoplasm Circulating Cells; Non-Invasive Detection; Paper; Patients; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Platinum; Procedures; Prognosis; Proteins; Protocols documentation; Publishing; RNA; Recurrence; Recurrent Malignant Neoplasm; Recurrent tumor; Sampling; Sensitivity and Specificity; Specimen; Techniques; Technology; Testing; Therapeutic Agents; Tissues; Transurethral Resection; Treatment Efficacy; Treatment outcome; Tumor Cell Biology; Tumor stage; Untranslated RNA; Urine; Urology; Xenograft Model; anticancer research; cancer cell; cancer recurrence; cancer therapy; cancer type; chemotherapy; clinical predictors; cost; cytotoxicity test; drug sensitivity; exosome; high risk; high throughput screening; high-throughput drug screening; improved; in vitro Model; invention; liquid biopsy; mortality; mutant; novel drug class; novel therapeutics; patient response; precision oncology; predicting response; promoter; response; standard care; standard of care; success; targeted treatment; three dimensional cell culture; Address; Adjuvant Chemotherapy; Biological Markers; Bladder; Bladder Neoplasm; Cancer Center; Cancer Detection; Cancer Patient; Cell Culture Techniques; Cells; Clinic; Clinical; Clinical Management; Clinical Treatment; Cystoscopy; Cytology; Data; Detection; Development; Diagnosis; Early Diagnosis; European; Exhibits; Funding; Goals; Health Personnel; Human; Human body; Immune; Immunotherapy; In Vitro; In complete remission; Intravesical Instillation; Laboratories; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical; Messenger RNA; Methods; MicroRNAs; Modeling; Monitor; Mutation; National Center for Advancing Translational Sciences; Nature; Neoadjuvant Therapy; Neoplasm Circulating Cells; Non-Invasive Detection; Paper; Patients; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Platinum; Procedures; Prognosis; Proteins; Protocols documentation; Publishing; RNA; Recurrence; Recurrent Malignant Neoplasm; Recurrent tumor; Sampling; Sensitivity and Specificity; Specimen; Techniques; Technology; Testing; Therapeutic Agents; Tissues; Transurethral Resection; Treatment Efficacy; Treatment outcome; Tumor Cell Biology; Tumor stage; Untranslated RNA; Urine; Urology; Xenograft Model; anticancer research; cancer cell; cancer recurrence; cancer therapy; cancer type; chemotherapy; clinical predictors; cost; cytotoxicity test; drug sensitivity; exosome; high risk; high throughput screening; high-throughput drug screening; improved; in vitro Model; invention; liquid biopsy; mortality; mutant; novel drug class; novel therapeutics; patient response; precision oncology; predicting response; promoter; response; standard care; standard of care; success; targeted treatment; three dimensional cell culture

PROJECT SUMMARY Bladder cancer (BC) is the costliest cancer (per case) among all cancer types and yet among the top 10 cancers it is the most underfunded cancer by NCI. There has been no significant improvement in overall survival and prognosis over the last thirty years except for the recent development of immunotherapy. At initial diagnosis, approximately 75% of cases are diagnosed at the non-muscle-invasive stages, and are usually treated with transurethral resection (TUR) followed by intravesical instillation of therapeutic agents into the bladder cavity in high risk patients. This approach is associated with cancer recurrence of over 60% at two years and progression into advanced stages in up to 25% of patients. Therefore, almost all patients will need long-term expensive cystoscopy. If a sensitive but less expensive method to detect cancer were available, it would improve the treatment outcomes and decrease the cost. For locally advanced BC, neoadjuvant chemotherapy is associated with a complete response of less than 40%. For metastatic BC, the response rate for the first-line platinum-based chemotherapy is approximately 50%. It is less than 20% for second-line chemotherapy. Currently no method is available to predict which patients will respond to therapy. Liquid biopsies are non-invasive methods that may be applicable for cancer precision medicine. Circulating factors, including circulating tumor cells (CTCs), cfDNAs, RNAs (miRNAs, long non-coding RNAs [lncRNAs], mRNAs), cell-free proteins, peptides, or exosomes et al., are derived from cells in human body. However, it is still unclear where and at what tumor stage these circulating molecules are coming from. There are still too many technical issues that limit the study of CTC biology and their applications. Our latest data show that we are able to generate conditionally reprogrammed cell cultures (CRC) from urine samples of 60 BC patients. Therefore, we will focus on CR technology for generating urine-derived cultures to predict efficacy of treatment and recurrence of BC. We will also determine if urine-derived cell cultures are a simpler and potentially more sensitive technique to monitor bladder cancer recurrence. Urine samples from 70-90 BC cases (prior to initial transurethral resection and chemotherapy) will be used to generate bladder cancer cultures. Following therapy, the patients will be monitored every 3 months (for a total of 2 years) by cystoscopy, and urine cell culture. By comparing the detection of recurrence by each of these techniques, we can determine whether cell culture and/or mutant hTERT detection can provide sufficient sensitivity and specificity to replace the expensive and invasive cystoscopy procedure. We will also use cell cultures derived from pre-surgery patients to evaluate for sensitivity to standard of care drugs and compared with the clinical response of the patient to these same drugs. Last, we will use CR cultures from non-responding patients or recurrent patients in unbiased high-throughput screening to identify and validate new potential therapies for BC.

项目摘要 膀胱癌（BC）是所有癌症类型中最昂贵的癌症（每例病例），但在十大癌症中 癌症是NCI最多的癌症。总体上没有显着改善 除了最近的免疫疗法发展外，过去三十年来的生存和预后。在初始 诊断，大约75％的病例是在非肌肉侵入性阶段诊断的，通常是 用经尿道切除（TUR）处理，然后在静脉内滴注治疗剂 高风险患者的膀胱腔。这种方法与两个时的癌症复发有关 多达25％的患者的年份和成长为高级阶段。因此，几乎所有患者都需要 长期昂贵的膀胱镜检查。如果有一种敏感但较便宜的检测癌症的方法，则 将改善治疗结果并降低成本。对于本地高级，新辅助 化学疗法的完全反应小于40％。对于BC转移性的响应率 对于一线铂的化学疗法约为50％。二线不到20％ 化学疗法。目前尚无预测哪些患者对治疗的反应。液体 活检是可能适用于癌症精确药物的无创方法。循环因素， 包括循环肿瘤细胞（CTC），CFDNA，RNA（miRNA，长无编码RNA [LNCRNA]，mRNA），MRNA）， 无细胞蛋白，肽或外泌体等人是从人体中的细胞衍生的。但是，仍然是 这些循环分子来自哪里，在哪个肿瘤阶段以及在哪个肿瘤阶段。还有太多 限制CTC生物学及其应用的技术问题。我们的最新数据表明我们是 能够从60名公元前患者的尿液样本中产生有条件重编程的细胞培养物（CRC）。 因此，我们将专注于CR技术来产生尿液来源的培养物以预测治疗的功效 和卑诗省的复发。我们还将确定尿液衍生的细胞培养是否更简单，可能更可能 监测膀胱癌复发的敏感技术。 70-90 BC病例的尿液样本（初始 尿道切除和化疗）将用于产生膀胱癌培养。下列的 治疗，将通过膀胱镜检查每3个月（总计2年）和尿液细胞对患者进行一次监测 文化。通过比较每种技术对复发的检测，我们可以确定细胞是否是否 培养和/或突变的HTERT检测可以提供足够的灵敏度和特异性来代替 昂贵且侵入性的膀胱镜检查程序。我们还将使用来自手术前患者的细胞培养物 评估对护理药物标准药物的敏感性，并将患者的临床反应与 这些相同的药物。最后，我们 将使用无反应患者或经常性患者的CR培养物 公正的高通量筛选，以识别和验证卑诗省的新潜在疗法。