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.
Public Health Relevance Statement: Public Health Relevance: 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. Oncotide Pharmaceuticals has discovered novel compounds that antagonize the activity of an oncogene that is overexpressed in breast cancer cells relative to normal adjacent tissue and potently and selectively induce cell death in cancer cells with minimal effects in normal cells. This proposal provides for testing of the lead compound in this series 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.
Project Terms: 1-Phosphatidylinositol 3-Kinase; Adverse effects; Agar; annexin A5; antitumor agent; Apoptosis; Apoptosis Regulator; Apoptotic; B-Lymphocytes; base; Binding (Molecular Function); Biological Assay; Breast Cancer Cell; Breast Cancer Treatment; Burkitt Lymphoma; c-myc Genes; cancer cell; Cancer cell line; Cancer Patient; cancer type; CD19 gene; Cell Count; Cell Death; Cell Death Process; cell growth; Cell Line; Cell Proliferation; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Clinical Trials; Clinical Trials Unit; Culture Media; cytotoxic; cytotoxicity; Data; Development; Diagnosis; Disease; Dose; Environment; Estrogen Receptor Status; Female; Genetic; Grant; Growth; Human; In Vitro; in vivo; Inflammation; inhibitor/antagonist; inorganic phosphate; Institutes; intravenous injection; Investigational New Drug Application; Killings; Lead; malignant breast neoplasm; Malignant Neoplasms; Mammary gland; MAPK8 gene; Measurement; Mediating; mitogen-activated protein kinase p38; Molecular Target; Monitor; Mus; MYC gene; NOD/SCID mouse; Normal Cell; Normal tissue morphology; novel; novel therapeutic intervention; Oncogene Proteins; Oncogenes; Outcome; overexpression; Paclitaxel; Palpitations; Pathway interactions; Peptides; Pharmacologic Substance; Pharmacopoeias; Phase; Phase I Clinical Trials; phosphatidylinositol 3-phosphate; Phosphorylation; Phosphotransferases; pre-clinical; prevent; Process; Propidium Diiodide; Protein Dephosphorylation; Protein phosphatase; protein phosphatase 2A inhibitor 2; Proteins; Proto-Oncogene Proteins c-myc; public health relevance; Regulation; Relative (related person); Reporting; SCID Mice; Series; Set protein; Signal Transduction; Signal Transduction Pathway; Staining method; Stains; Testing; Tissues; Titrations; Toxicology; Trypan Blue; tumor; tumor growth; Tumor Suppressor Proteins; Tumor Volume; tumor xenograft; tumorigenic; Ubiquitination; United States; Validation; Western Blotting; Woman; Work; Xenograft Model; Xenograft procedure
