The regulation and targeting of cell survival pathways in cancer

癌症细胞存活途径的调控和靶向

• 批准号: 9023035
• 负责人: Joshua Lyon Andersen
• 金额: $ 43.2万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-22 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9023035
• 关键词: Acetylation; Anthracyclines; Area; Autophagocytosis; Binding; Binding Proteins; Breast Cancer Cell; Cancer Biology; Cancer Patient; Catabolic Process; Cell Survival; Cellular Stress; Cessation of life; Clinical; Cytotoxic Chemotherapy; Data; Deacetylase; ERBB2 gene; Goals; Growth; HDAC6 gene; Hormones; Human; IGF1R gene; Intervention; Ischemia; Lysine; MAP Kinase Gene; Malignant Neoplasms; Mammary Neoplasms; Manuscripts; Mediating; Microscopy; Molecular; Molecular and Cellular Biology; Nutrient; Oncogenic; Outcome; PI3K/AKT; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphorylation; Phosphotransferases; Play; Process; Proteins; Proteomics; Public Health; Publishing; Regulation; Research; Resistance; Role; Series; Signal Transduction; Stress; Testing; Therapeutic; Transforming Growth Factor beta; Work; Xenograft procedure; chemotherapy; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; malignant breast neoplasm; mouse model; mutant; neoplastic cell; novel strategies; patient population; public health relevance; receptor; taxane; tool; trafficking; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor xenograft

 DESCRIPTION (provided by applicant): The dynamic ability of tumor cells to adapt to a variety of stresses, including ischemia and cytotoxic chemotherapies, ultimately leads to more aggressive tumor growth and chemoresistance. 14-3-3ζ, an oncogenic phospho-binding protein, is known to play a central role in this process, yet a fundamental gap exists in our understanding of 1) how 14-3-3ζ responds to stress to promote cell survival/adaptation; and 2) how 14-3-3ζ can be targeted to sensitize tumor cells to stress. Until this gap is filled, the therapeutic targeing of 14-3-3ζ to improve cancer outcomes will be unattainable. The long-term goal is to develop strategies to overcome chemoresistance in cancer and improve patient outcomes. The overall objective of this proposal is to understand a recently discovered 14-3-3ζ- mediated mechanism of autophagy control and develop strategies to inhibit 14-3-3ζ in breast cancer. The central hypothesis is that ischemia rearranges the 14-3-3ζ interactome to promote a ULK1- and AMPK-governed 14-3-3ζ interaction with phosphorylated Atg9A, which, in turn, promotes autophagy- mediated anthracycline resistance in triple negative breast cancer (TNBC). Additionally, from a therapeutic perspective, it is posited that inhibition of HDAC6, which deacetylates 14-3-3ζ at critical lysine residues, offers a novel strategy to broadly disrupt 14-3-3ζ interactions in breas tumors. Guided by strong preliminary data, this hypothesis will be tested in the following specific aims: 1) Determine the mechanism by which ULK1 and AMPK govern Atg9A activity and whether disrupting Atg9A phosphorylation overrides chemoresistance in TNBC; and 2) Target the mechanism of 14-3-3ζ acetylation to suppress 14-3-3ζ binding activity in vivo. In the first aim, a combination of proteomics, molecular and microscopy approaches will be used to determine the interplay between AMPK and ULK1 in the regulation of Atg9A phosphorylation and 14-3-3ζ binding. Additionally, a 14-3-3ζ-binding defective phosphomutant of Atg9A, which we have already established, will be used to determine whether abrogation of this mechanism blocks anthracycline resistance in TNBC. In aim 2, a clinically approved HDAC6 inhibitor will be tested for its ability to induce 14-3-3ζ acetylation and disrupt 14-3- 3ζ-mediated survival pathways in a series of patient derived TNBC xenografts. The approach is innovative because it has utilized 14-3-3ζ interactomics as a tool to understand adaptive mechanisms of cell survival. Moreover, the approach in aim 2 employs a completely novel strategy to block 14-3-3ζ in a patient-derived TNBC mouse model. The proposed research is significant because it will contribute fundamentally to our understanding of autophagy, an emerging mechanism of chemoresistance, and could ultimately yield 14-3-3ζ-targeted strategies to improve clinical outcomes in a patient population (triple negative breast cancer) with limited treatment options.