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

描述(申请人提供)：在美国，每年有超过27万名妇女被诊断出患有乳腺癌，超过4万人将死于这种疾病。虽然存在多种形式的乳腺癌，但大多数形式的乳腺癌都有一个共同的主题，即信号转导通路的异常，导致被称为细胞凋亡的程序性细胞死亡过程受到抑制。在正常的健康细胞中，细胞凋亡是一个精心调控的过程，这个过程有许多可诱导的正负调控因子。相反，许多类型的癌症的特点是异常，磷脂酰肌醇-3激酶(PI-3K)/Akt通路的结构性激活和c-Myc癌基因的过度表达。总而言之，这会导致在癌细胞中建立一个抗凋亡的环境，并与不良的结果相关。PI-3K/Akt通路的这种异常的结构性激活导致了大量的精力集中在该通路的抑制剂作为靶向抗肿瘤药物的开发上。Akt信号调节和c-Myc稳定的自然过程利用蛋白磷酸酶2A(PP2A)来去除激活Akt或稳定c-Myc的磷酸基团。不幸的是，通过基因缺失或其他机制，许多乳腺癌细胞中的PP2A活性降低。我们最近发现，一种有效的PP2A抑制剂SET癌蛋白在乳腺癌细胞中相对于邻近的正常组织过表达。此外，我们还发现了有效的SET拮抗剂，可以激活PP2A，导致c-Myc的不稳定和Akt下游信号的失活。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。这项建议提供了COG化合物作为抗肿瘤药物在小鼠异种移植模型中治疗乳腺癌的测试。如果提议的工作成功，它有可能在治疗乳腺癌的药典中增加新的分子靶向药物。这将对乳腺癌的治疗产生重大影响，因为分子靶向治疗通常副作用较少，有可能减轻癌症患者的极端身体负担，每年可以挽救数千人的生命。

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.