AKT-independent Pathways of Phosphoinositide 3-kinase dependent transformation

磷酸肌醇 3 激酶依赖性转化的 AKT 独立途径

基本信息

批准号：
8100267
负责人：
CHARLES L. SAWYERS
金额：
$ 43.5万
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：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8100267
关键词：
AKT inhibition Ablation Address Affect Alleles Androgen Receptor Androgens Antiandrogen Therapy Biochemical Biological Biological Assay Biological Markers Catalytic Domain Cell Line Cells Clinical Research Clinical Trials Combined Modality Therapy Complement Credentialing Data Epithelial Cells Event Eye Family Fibrous capsule of kidney Funding Future Gene Expression Profile Genes Genome Growth Human Knockout Mice Lead Lesion Libraries Lipids MAPK8 gene Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Mitogen-Activated Protein Kinases Mus Mutation Null Lymphocytes Output PTEN gene Pathway interactions Phenotype Phosphoinositide Pathway Phosphoric Monoester Hydrolases Phosphotransferases Play Pre-Clinical Model Property Prostate Protein Isoforms Proteins Proto-Oncogene Proteins c-akt RNA Interference Reagent Receptor Activation Research Personnel Resistance Role Second Messenger Systems Signal Transduction Therapeutic Tissue Recombination Transgenic Mice Transgenic Organisms base cDNA Library design gain of function mutation human FRAP1 protein inhibitor/antagonist loss of function mutation mTOR Inhibitor mTOR inhibition novel programs receptor function reconstitution research study second messenger small hairpin RNA small molecule success therapeutic target tumor tumor progression

项目摘要

Taken together, the discovery of either gain-of-function mutations in the p110cc catalytic subunit of PI3K or loss of function mutations in the PTEN lipid phosphatase 'credential' this pathway as a therapeutic target in many human cancers. The consequence of either mutation is an increase in the steady state level of PIPS, which functions as a second messenger to activate downstream effector pathways. Successful therapeutic targeting of this pathway requires a comprehensive understanding of the essential signaling events downstream of PIPS. Much data from our group and others supports the critical downstream roles of Akt and mTOR, which has resulted in translational clinical studies of mTOR inhibitors in PI3K pathway-driven tumors at UCLA and elsewhere. However, there are a number of observations that implicate other PIP3- regulated pathways, in conjunction with Akt, that could play critical roles in mediating the full transformation phenotype. This project will address this question in prostate cancer, with a particular focus on defining the role of the JNK family of MAP kinases in PISK-driven transformation and elucidating additional PIP3- dependent, Akt-independent pathways that regulate androgen receptor function. In Aims 1 and 2, we will evaluate the functional role of the JNK pathway in PI3K pathway-driven prostate cancer progression by: (i) expressing activated alleles of JNK in the mouse prostate, alone and in combination with additional lesions such as AKT, and (ii)targeting the JNK pathway (using small molecule inhibitors and RNA interference) in conditional PTEN mice with prostate cancer. Aim 3 will build upon observations by us and others showing crosstalk between kinase pathways and androgen receptor function, by defining PI3K-dependent pathways that regulate the AR function. These experiments will complement the efforts in Project 1 to define the direct transforming properties of distinct PI3K isoforms (Cantley/Roberts) and the efforts in Project 2 (Sellers) to characterize the distinct phenotypes of Akt activation versus PTEN loss in the mouse prostate. Collectively, these studies will inform the design of future clinical trials, with an eye toward rational combination therapy for PI3K pathway-driven prostate cancer.

综上 PTEN脂质磷酸酶的功能突变丧失该途径作为治疗目标许多人类癌症。这两种突变的结果是PIP的稳态水平的增加，它充当第二个使者，以激活下游效应器途径。成功的治疗性靶向这一途径需要对基本信号事件有全面的了解下游PIP。来自我们小组的大量数据和其他数据支持AKT的关键下游角色和MTOR，这导致了PI3K途径驱动的MTOR抑制剂的转化临床研究加州大学洛杉矶分校和其他地方的肿瘤。但是，有许多观察结果暗示了其他PIP3- 受规范的途径与AKT结合使用，可以在调解完整转换中起关键作用表型。该项目将在前列腺癌中解决这个问题，特别着眼于定义 JNK家族MAP激酶在Pisk驱动的转化中的作用，并阐明其他PIP3- 调节雄激素受体功能的依赖性，非AKT独立的途径。在目标1和2中，我们将评估JNK途径在PI3K途径驱动的前列腺癌进展中的功能作用：（i）单独并与其他病变相结合，表达小鼠前列腺中JNK的激活等位基因例如Akt，（ii）靶向JNK途径（使用小分子抑制剂和RNA干扰）有条件的PTEN小鼠患有前列腺癌。 AIM 3将以我们和其他显示的观察为基础通过定义PI3K依赖性途径，激酶途径和雄激素受体功能之间的串扰调节AR函数。这些实验将补充项目1中的努力来定义直接改变不同的PI3K同工型（Cantley/Roberts）和项目2（卖方）的努力的特性表征小鼠前列腺中Akt激活与PTEN损失的不同表型。共同这些研究将为未来临床试验的设计提供信息，并着眼于合理组合疗法用于PI3K途径驱动的前列腺癌。