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

通过 PP2A 再激活疗法靶向 c-Myc 和 Akt 治疗乳腺癌

• 批准号: 8454718
• 负责人: Dale J Christensen
• 金额: $ 30万
• 依托单位: ONCOTIDE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454718
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adverse effects; Agar; Apoptosis; Apoptosis Regulator; Apoptotic; B-Lymphocytes; Binding; Biological Assay; Breast Cancer Cell; Breast Cancer Treatment; Burkitt Lymphoma; CD19 gene; Cancer Patient; Cancer cell line; Cell Count; Cell Death; Cell Death Process; Cell Line; Cell Proliferation; Cells; Cessation of life; Chronic Lymphocytic Leukemia; Clinical Trials; Clinical Trials Unit; Culture Media; Data; Development; Diagnosis; Disease; Dose; Environment; Estrogen Receptor Status; Female; Genetic; Grant; Growth; Human; In Vitro; Inflammation; Institutes; Investigational New Drug Application; Lead; MAPK8 gene; MYC gene; Malignant Neoplasms; Mammary gland; Measurement; Mediating; Molecular Target; Monitor; Mus; NOD/SCID mouse; Normal Cell; Normal tissue morphology; Oncogene Proteins; Oncogenes; Outcome; Paclitaxel; Palpitations; Pathway interactions; Peptides; Pharmacologic Substance; Pharmacopoeias; Phase; Phase I Clinical Trials; Phosphorylation; Phosphotransferases; Process; Propidium Diiodide; Protein Dephosphorylation; Protein phosphatase; Proteins; Proto-Oncogene Proteins c-myc; 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 Suppressor Proteins; Tumor Volume; Ubiquitination; United States; Validation; Western Blotting; Woman; Work; Xenograft Model; Xenograft procedure; annexin A5; antitumor agent; base; c-myc Genes; cancer cell; cancer type; cell growth; cytotoxic; cytotoxicity; in vivo; inhibitor/antagonist; inorganic phosphate; intravenous injection; killings; malignant breast neoplasm; mitogen-activated protein kinase p38; novel; novel therapeutic intervention; overexpression; phosphatidylinositol 3-phosphate; pre-clinical; prevent; protein phosphatase 2A inhibitor 2; public health relevance; tumor; tumor growth; tumor xenograft; tumorigenic

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.

描述（由申请人提供）：在美国，每年有超过 270,000 名女性被诊断患有乳腺癌，超过 40,000 人将死于该疾病。虽然存在多种形式的乳腺癌，但大多数形式的一个共同主题涉及信号转导途径的异常，导致抑制称为细胞凋亡的程序性细胞死亡过程。细胞凋亡是正常健康细胞中一个精心调节的过程，该过程有许多可诱导的正调节因子和负调节因子。相比之下，许多类型的癌症都以磷脂酰肌醇-3 激酶 (PI-3K)/Akt 途径的异常、组成型激活和 c-Myc 癌基因过度表达为特征。总之，这会导致癌细胞中建立抗凋亡环境，并与不良结果相关。 PI-3K/Akt 途径的这种异常组成性激活导致人们投入大量精力致力于开发该途径的抑制剂作为靶向抗肿瘤药物。 Akt 信号传导和 c-Myc 稳定调节的自然过程利用蛋白磷酸酶 2A (PP2A) 去除激活 Akt 或稳定 c-Myc 的磷酸基团。不幸的是，许多乳腺癌细胞中的 PP2A 活性通过基因缺失或其他机制而降低。我们最近发现 SET 癌蛋白（一种有效的 PP2A 抑制剂）在乳腺癌细胞中相对于邻近正常组织过度表达。此外，我们还发现了 SET 的强效拮抗剂，可激活 PP2A，从而导致 c-Myc 不稳定和 Akt 下游信号失活。这些化合物以 90-200 nM 的效力诱导癌细胞凋亡，但在浓度高达 50 倍的剂量下不会杀死正常细胞。该提案规定在小鼠异种移植模型中测试 COG 化合物作为抗肿瘤药物治疗乳腺癌的效果。如果拟议的工作成功，它有可能在药典中添加新的分子靶向药物来治疗乳腺癌。这将对乳腺癌的治疗产生重大影响，并且由于分子靶向疗法通常副作用较少，因此有可能减轻癌症患者的极端身体负担，并且每年可以挽救数千人的生命。