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    Auger Electron Emitters for Breast Cancer Radioimmunotherapy

    Scientific Abstract:
    Auger Electron Emitters for Breast Cancer Radioimmunotherapy. Background: While radioimmunotherapy (RAIT) has been under investigation for >20 years, the great majority of the effort has been with beta-particle emitters. These have a long pathlength in tissue, and therefore produce a relatively high level of non-specific toxicity. This proposal is to further investigate the potential of emitters of low-energy electrons (LEEs), which includes some Auger and conversion electrons, having energies of approximately 10-40 keV. Suitable nuclides include 111In and 67Ga. In previous studies with B-lymphoma target cells, we demonstrated that this approach provided effective therapy in a mouse xenograft model. We recently demonstrated that carcinoma cells, including breast carcinoma cells, can be efficiently killed in vitro by Abs to EGFr (epidermal growth factor receptor) and HER-2 conjugated to 111In. Note that we use the term “Auger electron emitter”, as opposed to LEE emitter, in the title of this proposal, because this term is more widely recognized in the literature. Hypotheses: 1) That Abs labeled with LEE emitters can be effective therapeutic agents in mouse xenograft models of micrometastatic breast cancer, and that LEE emitters will be more effective than beta-particle emitters, due to their lower non-specific toxicity. 2) That mixed LEEs and beta-particles will provide the most effective therapy of macroscopic tumors. Specific Aims: With radiolabeled anti-EGFr and anti-HER-2, test 1) cytotoxicity in vitro of carcinoma cell lines; 2) experimental therapy of s.c. carcinoma xenografts in immunodeficient mice. Study Design: Therapy with either LEE or beta-particle emitters, or a mixture of both, will be tested. Tumors of different sizes will be tested, ranging from microscopic disease to large s.c. tumor masses, since the optimal conjugate is likely to depend on the tumor burden. Potential Outcomes and Benefits of the Research: Many breast cancer patients who are treated by surgery and chemotherapy still have microscopic residual disease which will eventually recur, and become life-threatening. This line of research is aimed at the therapy of such micrometastatic disease. If developed successfully, this approach has the potential to fully eradicate tumor cells in these patients.

    Lay Abstract:
    Auger Electron Emitters for Breast Cancer Radioimmunotherapy. Background: Many breast cancer patients who are treated by surgery and chemotherapy still have microscopic residual disease which will eventually recur, and become life-threatening. This research is aimed at the therapy of such microscopic disease. The basic strategy is to use antibodies (Abs) to specifically deliver radioactivity to cancer cells. However, it should be appreciated that this strategy, called radioimmunotherapy (RAIT), has been under investigation for >20 years, without dramatic success in the case of breast cancer (although it has been successful in the case of B-cell lymphoma). The novel aspect of this proposal is to utilize a different type of radionuclide, one emitting low energy electrons (LEEs). The great majority of the effort in RAIT has been with beta-particle emitters, which have a long pathlength in tissue, and therefore produce high levels of non-specific toxicity. After earlier work with B-lymphoma target cells, we recently demonstrated that carcinoma cells, including breast carcinoma cells, were efficiently killed by Abs to EGFr (epidermal growth factor receptor) and HER-2, conjugated to the LEE emitter 111In. In vitro and in vivo studies showed that LEE emitters killed tumor cells with less non-specific toxicity than beta-particle emitters. Hypotheses: 1) That Abs labeled with LEE emitters can be effective therapeutic agents in mouse models of disseminated breast cancer, and that LEE emitters will be more effective than beta-particle emitters, due to their lower non-specific toxicity. 2) That mixed LEEs and beta-particles will provide the most effective therapy of larger tumors. Specific Aims: With radiolabeled anti-EGFr and anti-HER-2, test 1) killing in vitro of carcinoma cell lines; 2) experimental therapy of subcutaneous cancer xenografts in mice. Study Design: Therapy with either LEE or beta-particle emitters, or a mixture of both, will be tested. Tumors of different sizes will be tested, ranging from microscopic disease to large subcutaneous tumor masses, since the optimal conjugate is likely to depend on the tumor burden. Potential Outcomes and Benefits of the Research: If developed successfully, this approach has the potential to fully eradicate tumor cells in breast cancer patients with residual microscopic disease.