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癌症。在介绍中，> 80％的膀胱肿瘤是器官构造的，在临床上分为两组。最常见的组是非肌肉侵入的肿瘤，约占病例的70-80％。该组由手术，新的或辅助的省级免疫疗法或化学疗法来管理。静脉治疗涉及通过留置导管将药物溶液灌输到膀胱中。复发很常见，发生在40％至80％的患者中。 10％至20％的复发伴随着等级和/或阶段进展（包括更致命的转移性疾病）。第二组是肌肉摄取的肿瘤，通过部分或完整的膀胱切除术（去除膀胱）来管理，该肿瘤具有很大的风险，并且不受老年患者的耐受性耐受。 用于静脉内治疗的最常用的化学治疗剂是丝裂霉素C（MMC）和阿霉素。通过一系列的临床前和临床研究，我们的小组确定它们的功效受到两个因素的限制：药物不足至肿瘤和低化学敏感性（尤其是对于更具侵略性的肿瘤）。接下来，我们确定了一种使用药代动力学（PK）干预措施来最大化MMC递送到非肌肉膀胱肿瘤的方法。该方法在多中心，随机的III期试验中进行了测试；结果证实了我们的假设，即改善药物递送可显着提高5年无复发率（从23.5％到42.6％）。这些数据还表明，对于未通过静脉内MMC治疗进行充分管理的其余患者需要一种新方法。 Survivin是膀胱癌侵袭性和复发性的标志物/预测指标。我们已经开发了一种用于Survivin siRNA的阳离子阳离子脂质载体（PCAT），该siRNA敲低培养细胞和含肿瘤动物的蛋白质表达，并增强了固体肿瘤中化学疗法的抗肿瘤活性。由于据报道，Survivin的抑制可以增强膀胱肿瘤对MMC的敏感性，因此我们建议评估MMC和PCAT-Survivin siRNA组合，作为产生出色的抗肿瘤活性的一种选择，并建议开发此组合以治疗非肌肉发明的膀胱癌癌。该R43项目的两个目标是确定将两种代理组合的最佳条件，并确定PCAT-SIRNA的适当给药途径（即静脉输注和/或粘膜下注射）。 公共卫生相关性：这个R43项目有可能导致新的治疗方式，并显着改善膀胱癌的治疗，而该疾病仍在膀胱中。鉴于这些患者的终身医疗保健费用极高（2003年美元超过100亿美元），额外的潜在收益是成本控制。

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