The goal of Project 2 is to continue translational research to develop combined modality radioimmunotherapy (CMIIIT) with curative intent for patients with breast and prostate cancer. Trials of single agent 131I-ChL6, 90Y- DOTA-peptide-ChL6 or 90Y21T-BAD-mI70 without and with peripheral blood stem cell support in patients with advanced breast or prostate cancer have provided evidence for therapeutic response, albeit brief, in the majority of patients. M170 reacts intensely with almost all breast and prostate adenocarcinomas when judged by immunohistopathology and nuclear imaging. Based on past work, proposed trials in breast and prostate cancer use: 1) 90Y-DOTA-peptide-m170 because its therapeutic index is about IO times that of the corresponding 13II~ labeled antibody; 2) high dose, fractionated RIT with peripheral blood stem cell support to deliver greater and more uniform tumor radiation; and 3) paclitaxel (Taxol) as a synergistic radiosensitizer to overcome p53 and BCL2 therapy resistance common in breast and prostate cancer. Patient-specific dosimetry will direct radionuclide dosing. In a nude mouse xenograft model with molecular aberrations comparable to those of human breast cancer, 90Y-DOTA-peptide conjugated antibody and Taxol, in doses clinically achievable in patients, provided therapeutic synergy without increased toxicity, when administered at the optimal time and sequence. When newer peptide-linked immunoconjugates to be generated in Project 3, using a peptide library, are shown promising in preclinical studies, a protocol will be developed to conduct clinical trials of these radiopharmaceuticals beginning in the next competitive submission. Similarly, preclinical trials of integrin binding peptides will be conducted to find additional agents synergistic with those already proposed. Integrin binding peptides induce neovascular apoptosis that may cause early vascular leak with increased tumor uptake. Later vascular collapse may increase retention of 90Y-DOTA-peptide-m170. Thereby, tumor radiation will be increased and there is potential for tumor vascular blockade. Strengths of this project include a cohesive team with a proven record in translational investigations of this type. Strategies developed in preclinical studies in Projects 1, 2, and Core C and novel peptide chemistry developments in Project 3 will provide further advances in CMRIT. Information from this project is relevant to the remainder of the Program Project and to other groups using CMRIT for cancer.
Showing the most recent 10 out of 187 publications
