Blocking Breast Cancer Progression with Radioactive Antibody

Institution: University of California, Irvine
Investigator(s): Michael Samoszuk, M.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1IB-0219 Award: $50,000
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure

Initial Award Abstract (1995)
Approximately 20% of human breast cancers are extensively infiltrated by a rare type of white blood cell called an eosinophil and contain extracellular deposits of an enzyme called eosinophil peroxidase (EPO). Coincidentally, EPO has vary significant structural similarity to lactoperoxidase, an enzyme that is naturally found in breast milk and that is secreted by lactating breast cells but not by the resting breast cells. We have developed a monoclonal antibody called EOS that binds to EPO and possibly to human lactoperoxidase but not to any other normal human tissues. Based on pilot study data, we hypothesize that EPO and/or lactoperoxidase are present at high levels within small nests of breast cancer in certain patients. Consequently, we propose that EOS antibody will be an ideal vehicle for specifically delivering radioactive materials to the EPO/lacto-peroxidase target within the nests of breast cancer. The radioactive material will then damage or destroy the cancer cells and blood vessels within the tumor, thereby preventing the progression of the cancer without causing significant systemic toxicity.

In order to test this hypothesis, we first intend to retrieve up to 300 archival specimens of benign breast conditions and breast cancers of different types. These tissue specimens will be tested for the presence of EPO and/or lactoperoxidase. We will then chemically attach EOS antibody to rhenium-188. This radioisotope was selected because it has a short half-life, does not accumulate in normal tissues, and can be effectively administered at low doses. Following the radio labeling, we will determine the physical properties of the radioactive antibody to determine if it will be suitable for human use. When completed, these preclinical feasibility studies will translate into a compelling rationale for initiating subsequent clinical trails of rhenium 188-EOS, a novel radiopharmaceu-tical that will have value for preventing disease progression in a subset of breast cancer patients whose tumors contain EPO deposits or lactoperoxidase.

Final Report (1996)
This project was intended to develop a novel strategy for preventing progression of breast cancer. In specific, we sought to document the presence of a new target in human breast cancer tissues (an enzyme called eosinophil peroxidase) and then to radiolabel a mouse monoclonal antibody directed against the new target. The radioisotope that we selected for this purpose (rhenium-188) has certain desirable physical properties that suggested that it could be used to destroy the cancer without causing significant systemic toxicity. We successfully attained the first objective by demonstrating for the first time that eosinophil peroxidase is extensively deposited within a majority of human breast cancers. This important finding immediately raised questions about the potential biological significance of the new target in breast cancers. One exciting possibility that was suggested by our findings is that the cells that deposit eosinophil peroxidase in breast cancers may also be responsible for promoting new blood vessel growth and "healing" around the rapidly expanding tumor. If this proves to be correct, then our findings could eventually be translated into other novel approaches for preventing the progression of breast cancers.

Although we were eventually able to label the monoclonal antibody with rhenium-188, the radiolabeling procedure greatly reduced the binding properties of the antibody. Thus, we sought to identify some alternate approaches for exploiting the natural presence of eosinophil peroxidase within breast cancers. One such approach that we investigated involved a drug called penicillamine that is currently used for the treatment of severe rheumatoid arthritis. We demonstrated in vitro that this drug is highly effective at killing tumor cells in the presence of eosinophil peroxidase, but that plasma proteins greatly reduce the anti-tumor efficacy of the drug in vivo. Another approach that we investigated was to radiolabel heparin with rhenium-188. Heparin is a drug that is already approved for human use and that binds strongly to eosinophil peroxidase. We successfully completed the radiolabeling and are now hoping to pursue studies with the heparin-rhenium complex in the future.

Occult deposition of eosinophil peroxidase in a subset of human breast carcinomas.
Periodical:American Journal of Pathology
Index Medicus: Am J Pathol
Authors: Samoszuk MK, Nguyen V, Gluzman I, Pham JH.
Yr: 1996 Vol: 148 Nbr: 3 Abs: Pg:701-6