TRIMODAL GENE THERAPY FOR PROSTATE CANCER

描述（改编自应用程序） 前列腺癌是男性最常见的恶性肿瘤。虽然 常规治疗（手术、放疗、雄激素消融）产生高 早期疾病的治愈率，许多肿瘤复发， 对于疾病的晚期仍然缺乏治疗方案。我们 一项研究计划开发了一种新颖的，多方面的基因治疗方法， 前列腺癌的治疗我们的方法利用了一个修改后的，复制 感受态腺病毒（FGR）选择性和有效地递送一对 前列腺肿瘤的治疗性自杀基因。动物临床前研究 已经证明FGR病毒本身产生有效的抗肿瘤作用， 通过在人前列腺癌细胞中复制并优先破坏 缺乏功能性p53肿瘤抑制蛋白。的疗效 FGR病毒可以通过激活两个自杀基因系统（CD/5 FC和 HSV 1 TK/GCV），其使恶性细胞对特异性 药理学试剂（前药），更重要的是，使它们对 辐射我们的方法的优点在于，它同时利用了 三种形式的病毒，双自杀基因，和放射治疗， 选择性地破坏前列腺癌细胞，对正常细胞的毒性最小， 组织中 我们的研究工作目前正处于临床前/I期临床的尖端 问题研究涉及FGR病毒伴随的I期临床方案 双重前体药物治疗已经被我们的IRB批准。IND前会议 FDA已经举行，我们预计在1999年开始I期试验。作为一种手段来 为了进一步提高我们方法的有效性，该应用程序将：1） 评价增加雄激素消融术作为第四治疗组的优点，2） 评估FGR病毒治疗对播散性疾病的有效性， 和3）评价每个治疗组对肿瘤的特异性 p53状态，并确定治疗失败是否与p53状态相关。

DESCRIPTION (adapted from application) Prostate cancer is the most commonly diagnosed malignancy in men. Although conventional therapies (surgery, radiation, androgen ablation) produce high cure rates of early stage disease, many tumors recur and an effective therapeutic regimen is still lacking for advanced stages of the disease. Our research program has developed a novel, multifaceted, gene therapy approach for the treatment of prostate cancer. Our approach utilizes a modified, replication competent adenovirus (FGR) to selectively and efficiently deliver a pair of therapeutic suicide genes to prostate tumors. Preclinical studies in animals have demonstrated that the FGR virus itself generates a potent antitumor effect by replicating in and preferentially destroying human prostate cancer cells that lack a functional p53 tumor suppressor protein. The therapeutic effect of the FGR virus can be enhanced by invoking two suicide gene systems (CD/5FC and HSV1 TK/GCV), which render malignant cells sensitive to specific pharmacological agents (prodrugs), and more importantly, sensitizes them to radiation. A strength of our approach is that it simultaneously makes use of three modalities viral, double suicide gene, and radiation therapies to selectively destroy prostate cancer cells with minimal toxicity towards normal tissues. Our research efforts are currently at the cusp of preclinical/phase I clinical studies. A phase I clinical protocol involving the FGR virus concomitant with double prodrug therapy has been approved by our IRB. A pre-IND meeting with the FDA has been held, and we expect to begin phase I trials in 1999. As a means to further enhance the efficacy of our approach, this application will: 1) evaluate the merit of adding androgen ablation as a fourth therapeutic arm, 2) evaluate the effectiveness of FGR viral therapy against disseminated disease, and 3) evaluate the specificity of each therapeutic arm with respect to tumor p53 status and determine whether treatment failure correlates with p53 status.