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: 10395552
• 负责人: Xuefeng Liu
• 金额: $ 37.94万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395552
• 关键词: Address; Biological Markers; Bladder; Bladder Neoplasm; Cancer Center; 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 Cancer Detection; Operative Surgical Procedures; Paper; Patients; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Platinum; Procedures; Proteins; Protocols documentation; Publishing; RNA; Recurrence; 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; base; 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; liquid biopsy; mortality; mutant; novel drug class; novel therapeutics; patient response; precision oncology; predicting response; prognostic of survival; promoter; response; standard care; standard of care; success; targeted treatment; three dimensional cell culture; tumor

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）是所有癌症类型中成本最高的癌症（每例），但也是前10名 它是NCI资助最不足的癌症。总体而言， 在过去的三十年中，除了免疫疗法的最近发展之外，在初始 在诊断中，大约75%的病例在非肌肉侵入性阶段被诊断出来，并且通常 经尿道切除术（TUR）治疗，然后将治疗剂膀胱内滴入 膀胱腔高危患者。这种方法与两个月内超过60%的癌症复发有关。 25%的患者进展为晚期。因此，几乎所有患者都需要 长期昂贵的膀胱镜检查。如果有一种灵敏但便宜的方法来检测癌症， 将改善治疗效果并降低成本。对于局部晚期BC，新辅助治疗 化疗与小于40%的完全反应相关。对于转移性BC， 一线铂类化疗的有效率约为50%。二线不到20% 化疗目前还没有方法可以预测哪些患者会对治疗产生反应。液体 活组织检查是可应用于癌症精确医学的非侵入性方法。循环因子， 包括循环肿瘤细胞（CTC）、cfDNA、RNA（miRNA，长非编码RNA [lncRNA]，mRNA）， 无细胞蛋白质、肽或外来体等，是从人体细胞中提取的。但是依然 目前还不清楚这些循环分子来自哪里以及处于什么肿瘤阶段。仍然有太多 限制CTC生物学研究及其应用的技术问题。最新数据显示， 能够从60名BC患者的尿样中产生条件重编程细胞培养物（CRC）。 因此，我们将专注于CR技术，用于产生尿源性培养物，以预测治疗效果 和BC复发。我们还将确定尿源性细胞培养是否是一种更简单， 监测膀胱癌复发的敏感技术。70-90例BC病例的尿液样本（初始 经尿道切除术和化疗）将用于产生膀胱癌培养物。以下 治疗期间，患者将每3个月（共2年）通过膀胱镜检查和尿细胞检查进行监测。 文化通过比较这些技术中的每一种对复发的检测，我们可以确定细胞是否 培养物和/或突变hTERT检测可以提供足够的灵敏度和特异性以代替常规的检测。 昂贵且侵入性的膀胱镜检查程序。我们还将使用来自术前患者的细胞培养物 评价对标准治疗药物的敏感性，并与患者对以下药物的临床反应进行比较： 同样的药物。最后我们 将使用来自无应答患者或复发患者的CR培养物， 无偏见的高通量筛选，以确定和验证新的潜在治疗BC。