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.
Public Health Relevance Statement: 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.
NIH Spending Category: Cancer; Clinical Research; Urologic Diseases
Project Terms: Accounting; aggressive therapy; Animals; Applications Grants; Bacterial Toxins; Bladder; Bladder Neoplasm; cancer cell; cell killing; Cells; Cessation of life; Chimeric Proteins; Clinic; Cystectomy; Data; design; Diphtheria Toxin; Effectiveness; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Excision; Fusion Toxin; Growth; Harvest; Hour; Human; Image; Immunocompetent; Immunocompromised Host; Implant; in vivo; Killings; Laboratories; Luciferases; Malignant neoplasm of urinary bladder; Malignant Neoplasms; Modeling; mouse model; Mus; novel; novel strategies; Nude Mice; overexpression; Patients; Phase; Phase II Clinical Trials; prevent; Procedures; Production; Proteins; public health medicine (field); Recurrence; Research; research study; Safety; SCID Mice; Small Business Innovation Research Grant; Specimen; Tissues; Toxicity Tests; Toxicology; Toxin; Transplantation; tumor; tumor growth; tumor xenograft; Work; Xenograft procedure
