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

描述(申请人提供)：膀胱癌是美国第四大常见癌症。在临床表现上，80%的膀胱肿瘤是器官受限的，临床上分为两组。最常见的是非肌肉侵袭性肿瘤，约占病例的70-80%。这组患者接受手术治疗，外加新生或佐剂膀胱内免疫治疗或化疗。膀胱内治疗包括通过留置导尿管将药物溶液注入膀胱。复发很常见，40%到80%的患者会复发。10%到20%的复发伴随着分级和/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，采用部分或完全膀胱切除术(切除膀胱)，风险很大，老年患者不能很好地耐受。最常用的膀胱内化疗药物是丝裂霉素C(MMC)和阿霉素。通过一系列临床前和临床研究，我们的小组已经确定其疗效受到两个因素的限制：对肿瘤的药物输送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传递给非肌肉侵袭性膀胱肿瘤。这种方法在一项多中心、随机的III期试验中进行了测试；结果证实了我们的假设，即改善药物输送显著提高了5年无复发率(从23.5%提高到42.6%)。这些数据还表明，对于那些没有得到MMC膀胱内治疗的患者来说，需要一种新的治疗方法。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阳离子脂质载体(PCAT)，它可以抑制Survivin siRNA在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。由于已有报道抑制Survivin可增强膀胱肿瘤对MMC的敏感性，我们建议评估MMC和PCAT-Survivin siRNA联合应用可产生更好的抗肿瘤活性，并建议将其用于非肌肉浸润性膀胱癌的治疗。R43项目的两个目标是确定结合两种药物的最佳条件和确定PCAT-siRNA的适当给药途径(即膀胱内滴注和/或粘膜下注射)。 公共卫生相关性：这个R43项目有可能导致一种新的治疗方式，并在膀胱癌仍局限于膀胱的情况下显著改善膀胱癌的管理。鉴于这些患者的终生保健成本极高(按2003年美元计算超过100亿美元)，另一个潜在的好处是成本控制。

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.