Targeting c-Myc and Akt with PP2A reactivation therapy for the treatment of breas

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DESCRIPTION (provided by applicant): Each year in the United States over 270,000 women will be diagnosed with breast cancer and over 40,000 will die from the disease. While multiple forms of breast cancer exist, a common theme in most of the forms involves aberrations in signal transduction pathways that lead to inhibition of the programmed cell death process known as apoptosis. Apoptosis is a carefully regulated process in the normal healthy cell with many inducible positive and negative regulators of the process. In contrast, many types of cancer feature aberrant, constitutive activation of the Phosphatidylinositol-3 Kinase (PI- 3K)/Akt pathway and overexpression of the c-Myc oncogene. Together, this results in establishment of an anti-apoptotic environment in the cancer cell and correlates with poor outcome. This abnormal constitutive activation of the PI-3K/Akt pathways has lead to a great deal of effort being focused on development of inhibitors of this pathway as targeted anti-tumor agents. The natural process for regulation of Akt signaling and c-Myc stabilization utilizes Protein Phosphatase 2A (PP2A) to remove the phosphate groups that either activate Akt or stabilize c-Myc. Unfortunately, PP2A activity is reduced in many breast cancer cells through genetic deletion or other mechanisms. We recently found that the SET oncoprotein, a potent PP2A inhibitor, is overexpressed in breast cancer cells relative to adjacent normal tissue. Additionally we have found potent antagonists of SET that activate PP2A, which leads to destabilization of c-Myc and deactivation of downstream signals from Akt. These compounds induce apoptosis in cancer cells with 90-200 nM potency but do not kill normal cells at doses up to 50-fold higher concentrations. This proposal provides for testing of COG compounds as anti-tumor agents for the treatment of breast cancer in murine xenograft models. If the proposed work is successful, it has the potential to add novel molecular targeted agents to the pharmacopeia for treatment of breast cancer. This would have a significant impact on treatment of breast cancer, and because molecular targeted therapies typically have fewer side effects, would have the potential to reduce the extreme physical burden on the cancer patient and could save thousands of lives each year.