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

描述（由申请人提供）：膀胱癌是美国第四大常见癌症。膀胱肿瘤首发时，bbb80 %为器官局限型，临床分为两组。最常见的是非肌肉侵袭性肿瘤，约占病例的70-80%。本组采用手术加新或辅助膀胱内免疫治疗或化疗。膀胱内治疗包括通过留置导管将药物溶液注入膀胱。复发是常见的，发生在40%至80%的患者。10%至20%的复发伴有分级和/或分期进展（包括更致命的转移性疾病）。第二组，肌肉侵入性肿瘤，通过部分或完全膀胱切除术（膀胱切除）来治疗，这有很大的风险，老年患者不能很好地耐受。最常用的囊内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，我们小组已经确定了它们的疗效受到两个因素的限制：肿瘤给药不足和低化疗敏感性（特别是对更具侵袭性的肿瘤）。接下来，我们确定了一种使用药代动力学（PK）干预的方法，以最大限度地将MMC输送到非肌肉侵入性膀胱肿瘤。该方法在一项多中心随机III期试验中得到验证；结果证实了我们的假设，即改善给药方式可显著提高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治疗不充分的剩余患者，需要一种新的方法。Survivin是膀胱癌侵袭性和复发的标志物/预测因子。我们开发了一种聚乙二醇化的survivin siRNA阳离子脂质载体（PCat），该载体可以抑制survivin siRNA在体外培养细胞和载瘤动物体内的表达，增强化疗对实体肿瘤的抗肿瘤活性。由于已有报道称，抑制survivin可增强膀胱肿瘤对MMC的敏感性，因此我们建议评估MMC和PCat-survivin siRNA组合作为一种产生优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。本R43项目的两个目标是确定两种药物联合的最佳条件，以及确定PCat-siRNA的适当给药途径（即膀胱内滴注和/或粘膜下注射）。

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.