Novel regulation of PI3K/Akt to direct targeted breast cancer therapies

PI3K/Akt 的新调控可指导乳腺癌靶向治疗

基本信息

批准号：
10390306
负责人：
Wenyi Wei
金额：
$ 40.73万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-16 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390306
关键词：
AKT Signaling Pathway AKT inhibition Ablation Address Advocate Asparagine Automobile Driving Breast Cancer Patient Breast Cancer therapy Bypass Cancer Patient Cell Cycle Regulation Cells Clinic Clinical Trials Collaborations Combined Modality Therapy Cyclin A DNA DNA Damage Data Dose-Limiting Drug Targeting EGF gene Epigenetic Process FRAP1 gene Feedback Funding Genetic Genetic Transcription Goals Growth Growth Factor Homologous Gene Human Hydroxylation Hyperactivity Hypoxia In Vitro Insulin Interruption Link Lysine Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Mediating Metabolic Methylation Methyltransferase Molecular Mutation Nonhomologous DNA End Joining Oncogenic PI3K/AKT PIK3CA gene PTEN gene Pathologic Pathologic Processes Pathway interactions Phenotype Phosphorylation Phosphotransferases Physiological Physiological Processes Play Post-Translational Regulation Protein Kinase Proteins Proto-Oncogene Proteins c-akt Regulation Research Personnel Resistance Resolution Role S-Phase Fraction SETDB1 gene SKP2 gene Signal Pathway Signal Transduction Stimulus Toxic effect Transferase Transgenic Mice Translations Treatment outcome Ubiquitination Work Xenograft Model Xenograft procedure base breast tumorigenesis cancer initiation chemotherapy design endoplasmic reticulum stress epigenetic regulation experimental study genetic signature glycosylation glycosyltransferase histone methylation histone methyltransferase in vivo in vivo Model individual patient inhibitor inhibitor therapy mTOR Inhibitor malignant breast neoplasm mouse model mutant new therapeutic target non-histone protein novel pre-clinical prevent protein folding repaired response targeted agent targeted treatment therapeutic target tumor tumor growth tumor progression tumorigenesis

项目摘要

PI3K/AKT/mTOR signaling is critical for the cancer initiation and progression. Aberrant PI3K/AKT/mTOR hyperactivation has been documented in a large proportion of breast cancer patients. However, PI3K/AKT inhibitors have shown limited efficacy in the clinic, due to dose-limiting toxicities and emergence of resistance. Thus, identification of aberrant mechanisms of upstream regulation of AKT and identification of downstream mechanisms of PI3K/AKT signal relay to phenotypes associated with malignancy, remains critical. Epigenetic regulation plays an important role in tumorigenesis, and inhibitors targeting epigenetic factors are in clinical trials. Methylation of histones as well as non-histone proteins has been shown to play a functionally pivotal role in human cancers, including breast cancer. However, whether oncogenic signaling pathways, including PI3K/AKT/mTOR, are subject to methylation-dependent regulation has not been explored. Our preliminary data show that AKT undergoes lysyl methylation, a novel mode of regulation that contributes to protein kinase activation in breast cancer. Depletion of the histone methyltransferase SETDB1 reduces AKT activity, suggesting that SETDB1 could be a novel therapeutic target for PI3K/AKT-driven breast cancers. Therefore, in Aim 1 we propose that aberrant expression of SETDB1 in breast cancer contributes to hyperactivation of AKT in a methylation-dependent manner. We will define mechanistically how SETDB1 functions as a novel upstream regulatory mechanism that promotes AKT activation. We will further examine whether genetic ablation of SETDB1 suppresses proliferation in vitro and in vivo. Gene transcription, protein translation and metabolic reprogramming are known to mediate PI3K/AKT/mTOR signaling in cancer. Our preliminary studies have uncovered a previously unrecognized mechanism, whereby the N-glycosyl transferase ALG3 (asparagine-linked glycosylation 3 homolog), is co- amplified with PIK3CA in breast tumors, tightly correlates with a proliferative gene signature in breast cancers and is phosphorylated downstream of PI3K/AKT/mTOR. Deregulation of ALG3 induces ER stress leading to activation of the unfolded protein response (UPR). Thus, in Aim 2, we propose that ALG3 is a functional target of PI3K/AKT/mTOR/S6K1 signaling, and that hyperactivation of this pathway is required to meet the demands of increased protein translation, thereby reducing ER stress. We will determine the mechanism by which PI3K/mTOR signaling regulates ALG3 function and perform functional glycomics in vitro and in vivo. We will determine the contribution of ALG3 to growth in pathway-mutant cells and use combination therapy approaches with PI3K/AKT/mTOR inhibitors and drugs that block ER stress/UPR. The proposed studies will provide the molecular basis and rationale for developing more effective targeted therapies by suppressing the PI3K/AKT pathway based on individual patients’ signaling signatures to achieve better treatment outcome.

PI3K/AKT/MTOR信号传导对于癌症倡议和进展至关重要。异常PI3K/AKT/MTOR 在很大一部分乳腺癌患者中已经记录了过度激活。但是，PI3K/AKT 由于剂量限制毒性和耐药性出现，抑制剂在诊所的效率有限。那就是鉴定AKT上游调节的异常机制和下游识别 PI3K/AKT信号继电器与恶性肿瘤相关的表型的机制仍然至关重要。表观遗传调节在肿瘤发生中起重要作用，针对表观遗传因素的抑制剂是在临床试验中。组蛋白的甲基化以及非历史蛋白的蛋白质已显示出在功能上发挥作用包括乳腺癌在内的人类癌症中的关键作用。但是，是否致癌信号通路，包括PI3K/AKT/MTOR在内，尚未探索依赖甲基化的调节。我们的初步数据表明，AKT经历了赖氨酸甲基化，这是一种新型调节方式，有助于乳腺癌中的蛋白激酶激活。组蛋白甲基转移酶SETDB1的耗竭减少了Akt 活动，表明SETDB1可能是PI3K/AKT驱动乳腺癌的新型治疗靶点。因此，在AIM 1中，我们提出，乳腺癌中setDB1的异常表达有助于 Akt以甲基化依赖性方式过度激活。我们将机械定义如何setDB1 作为一种促进AKT激活的新型上游调节机制。我们将进一步检查 SetDB1的遗传消融是否会抑制体外和体内的增殖。已知基因转录，蛋白质翻译和代谢重编程已知癌症中的PI3K/AKT/MTOR信号传导。我们的初步研究已经发现了先前未被认可的 N-糖基转移酶ALG3（天冬酰胺连接糖基化3同源物）的机制是共同的在乳腺肿瘤中用pik3ca扩增，与增生剂紧密相关并在PI3K/AKT/MTOR的下游磷酸化。解除ALG3的管制会影响ER应力导致展开的蛋白质反应（UPR）的激活。在AIM 2中，我们建议ALG3是功能性目标 PI3K/AKT/MTOR/S6K1信号传导以及该途径的过度激活需要满足需求蛋白质翻译增加的增加，从而减少了ER应力。我们将确定哪种机制 PI3K/MTOR信号传导调节ALG3功能并在体外和体内执行功能性胶囊。我们将确定ALG3在途径突变细胞中生长的贡献并使用组合疗法使用PI3K/AKT/MTOR抑制剂和阻断ER应力/UPR的药物接近。拟议的研究将提供分子基础和基本原理，以通过抑制来开发更有效的靶向疗法 PI3K/AKT途径基于单个患者的信号标志，以获得更好的治疗结果。