DT-EGF Toxic Fusion Protein for Treatment of Bladder Cancer

描述（由申请人提供）：膀胱癌是美国第四大常见癌症，每年约有70,000例新病例和约15,000例死亡。浅表性膀胱癌经切除加卡介苗治疗，约有40%的复发病例不成功，最终需要膀胱切除术或其他积极治疗。与正常尿上皮细胞相比，膀胱癌过度表达表皮生长因子（EGF）受体，这为表皮生长因子导向的毒素治疗提供了一个靶点。DAB389EGF是一种融合毒素，它将含有a链和部分b链的修饰白喉毒素与羧基末端被EGF取代的白喉毒素结合在一起。该蛋白已被证明具有杀死EGF受体表达细胞的活性，可以在我们合作者的GMP设施中生产。目前的拨款申请将证明1)DT-EGF在免疫功能正常的小鼠模型中治疗原位同源性肿瘤与BCG一样有效，2)DT-EGF可以在免疫功能低下的动物中杀死原位人类膀胱癌植入物。这些实验将为我们提供必要的原理证明数据，以证明在进行适当的毒理学研究后，向FDA申请IND以进行人体II期试验是合理的。

DESCRIPTION (provided by applicant): Bladder cancer is the 4th most common cancer in the U.S. Accounting For ~70,000 new cases annually and ~15,000 deaths. Treatment of superficial bladder cancer by resection and BCG administration is unsuccessful in about 40% of cases with recurrences that eventually require cystectomy or other aggressive therapy. Bladder cancers overexpress the epidermal growth factor (EGF) receptor in comparison to normal uroepithelium, providing a target for treatment with EGF-directed toxins. DAB389EGF is a fusion toxin that combines modified diphtheria toxin containing the A-chain and partial B-chain with carboxy terminus replaced with EGF. This protein has proven activity in killing EGF receptor expressing cells, and can be produced in our collaborators' GMP facility. The present grant application will demonstrate 1) that DT--EGF is as effective as BCG in an immunocompetent mouse model in treating orthotopic syngenic tumors, and 2) that DT-EGF can kill orthotopic human bladder cancer implants in an immunocompromised animal. These experiments will provide us the necessary proof-of-principle data to justify pursuit of an IND with the FDA to perform a phase II trial in humans following appropriate toxicology studies. PUBLIC HEALTH RELEVANCE: Bladder cancer is a major public health challenge in the U.S. Accounting for 70,000new cases and 15,000 deaths annually. This project will develop a novel therapy that targets bladder cancer cells for killing by use of a bacterial toxin fused to the EGF receptor which is overexpressed in bladder tumors. By instillation of this agent into the bladders of mice bearing tumors, we will demonstrate that this novel approach can delay or prevent bladder cancer from progressing to its lethal invasive state.