Combination chemo-siRNA gene therapy of nonmuscle-invading bladder cancer

非肌肉侵袭性膀胱癌的联合化疗-siRNA 基因治疗

• 批准号: 8121224
• 负责人: Jessie L.-S. Au
• 金额: $ 34.45万
• 依托单位: OPTIMUM THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-08 至 2016-09-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121224
• 关键词: Accounting; Adjuvant; Animals; Bladder; Bladder Neoplasm; Bladder Tissue; Bladder Urothelium; Botox; Bypass; Canis familiaris; Carcinoma in Situ; Clinical Research; Cost Control; Cultured Cells; Cystectomy; Data; Disease; Dose; Doxorubicin; Drug Delivery Systems; Drug Kinetics; Early Diagnosis; Electrocoagulation; Embolism; Excision; Health Care Costs; Ileus; Immunotherapy; Indwelling Catheter; Injection of therapeutic agent; Intervention; Intravesical Instillation; Invaded; Lamina Propria; Lead; Lipids; Location; Lung; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Methods; Mitomycins; Modality; Morbidity - disease rate; Muscle; Myocardial Infarction; Neoadjuvant Therapy; Operative Surgical Procedures; Organ; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Postoperative Period; Preparation; Randomized; Recurrence; Reporting; Risk; Route; Series; Small Interfering RNA; Solid Neoplasm; Solutions; Staging; Stroke; Surface; Survivors; Testing; Tissues; Treatment Efficacy; Urothelium; base; chemotherapeutic agent; chemotherapy; follow-up; gene therapy; improved; intravesical; mortality; novel strategies; older patient; preclinical study; protein expression; research clinical testing; small hairpin RNA; survivin; tumor

DESCRIPTION (provided by applicant): Bladder cancer is the fourth most common cancer in the US. At presentation, >80% of bladder tumors are organ-confined, separated clinically into two groups. The most common group is the nonmuscle-invading tumors, accounting for about 70-80% of cases. This group is managed by surgery, plus neo- or adjuvant intravesical immunotherapy or chemotherapy. Intravesical therapy involves instilling a drug solution into the bladder through an indwelling catheter. Recurrence is common and occurs in 40 to 80% of patients. Between 10 to 20% of recurrences are accompanied by grade and/or stage progression (including the more fatal metastatic disease). The second group, the muscle-invading tumors, is managed by partial or complete cystectomy (removal of bladder), which presents significant risks and is not well tolerated by older patients. The most commonly used chemotherapeutic agents for intravescial therapy are mitomycin C (MMC) and doxorubicin. Through a series of preclinical and clinical studies, our group has established that their efficacy is limited by two factors: inadequate drug delivery to tumors and low chemosensitivity (especially for the more aggressive tumors). We next identified a method that uses pharmacokinetic (PK) interventions to maximize the MMC delivery to nonmuscle-invading bladder tumors. This method was tested in a multi-center, randomized phase III trial; the results confirm our hypothesis that improving the drug delivery significantly improves the 5-yr recurrence-free rate (from 23.5% to 42.6%). These data also indicate that a new approach is needed for the remaining patients who are not adequately managed by intravesical MMC therapy. Survivin is a marker/predictor of bladder cancer aggressiveness and recurrence. We have developed a pegylated cationic lipid carrier (PCat) for survivin siRNA that knockdowns the protein expression in cultured cells and in tumor-bearing animals, and enhances the antitumor activity of chemotherapy in solid tumors. Because it has been reported that inhibition of survivin enhances the sensitivity of bladder tumors to MMC, we propose to evaluate the MMC and PCat-survivin siRNA combination as an option to produce superior antitumor activity and propose to develop this combination for treating nonmuscle-invading bladder cancer. The two aims of this R43 project are to identify the optimal conditions for combining the two agents and to identify the appropriate administration route for PCat-siRNA (i.e., intravesical instillation and/or submucosal injection). PUBLIC HEALTH RELEVANCE: This R43 project has the potential to lead to a new treatment modality and significantly improve the management of bladder cancer while the disease is still localized in the bladder. Given the extremely high lifetime health care costs for these patients (over $10 billion in 2003 dollars), an additional potential benefit is cost containment.

描述（由申请人提供）：膀胱癌是美国第四大常见癌症。目前，>80% 的膀胱肿瘤局限于器官，临床上分为两组。最常见的是非肌肉侵犯性肿瘤，约占病例的 70-80%。该组通过手术加上新的或辅助的膀胱内免疫治疗或化疗进行治疗。膀胱内治疗涉及通过留置导管将药物溶液滴入膀胱。复发很常见，40% 至 80% 的患者会出现复发。 10% 至 20% 的复发伴有级别和/或分期进展（包括更致命的转移性疾病）。第二组是肌肉侵袭性肿瘤，通过部分或完全膀胱切除术（切除膀胱）进行治疗，这存在很大的风险，并且老年患者的耐受性不好。 膀胱内治疗最常用的化疗药物是丝裂霉素 C (MMC) 和阿霉素。通过一系列的临床前和临床研究，我们的团队已经确定它们的疗效受到两个因素的限制：对肿瘤的药物输送不足和化疗敏感性低（特别是对于更具侵袭性的肿瘤）。接下来，我们确定了一种使用药代动力学 (PK) 干预措施来最大限度地向非肌肉侵入性膀胱肿瘤输送 MMC 的方法。该方法在多中心、随机 III 期试验中进行了测试；结果证实了我们的假设，即改善药物输送可显着提高 5 年无复发率（从 23.5% 提高到 42.6%）。这些数据还表明，对于膀胱内 MMC 治疗未得到充分治疗的其余患者，需要一种新方法。 生存素是膀胱癌侵袭性和复发的标记/预测。我们开发了一种用于生存素 siRNA 的聚乙二醇化阳离子脂质载体 (PCat)，可降低培养细胞和荷瘤动物中的蛋白表达，并增强实体瘤化疗的抗肿瘤活性。因为据报道，抑制生存素可增强膀胱肿瘤对 MMC 的敏感性，因此我们建议评估 MMC 和 PCat-生存素 siRNA 组合作为产生卓越抗肿瘤活性的选择，并建议开发这种组合用于治疗非肌肉侵袭性膀胱癌。该 R43 项目的两个目标是确定组合两种药物的最佳条件，并确定 PCat-siRNA 的适当给药途径（即膀胱内滴注和/或粘膜下注射）。 公共健康相关性：该 R43 项目有可能带来一种新的治疗方式，并显着改善膀胱癌的治疗，而该疾病仍局限于膀胱。鉴于这些患者的终生医疗保健费用极高（按 2003 年美元计算超过 100 亿美元），另一个潜在的好处是控制成本。

项目成果

Intravenous siRNA Silencing of Survivin Enhances Activity of Mitomycin C in Human Bladder RT4 Xenografts.

• DOI: 10.1016/j.juro.2015.02.036
• 发表时间: 2015-07
• 期刊: The Journal of urology
• 作者: Cui M;Au JL;Wientjes MG;O'Donnell MA;Loughlin KR;Lu Z
• 通讯作者: Lu Z