Targeting the p110beta Isoform of PI3 Kinase in Pten Null Tumors

靶向 Pten 无效肿瘤中 PI3 激酶的 p110beta 同工型

基本信息

批准号：
8601056
负责人：
Jean Zhao
金额：
$ 40.12万
依托单位：
DANA-FARBER CANCER INST
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：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8601056
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Adverse effects Attention Automobile Driving B-Lymphocytes Blood Glucose Canis familiaris Catalytic Domain Cause of Death Clinic Clinical Trials Communities Coupled Data Enzymes Exhibits Funding Generations Genetic Genetic Engineering Genetic Models Goals Grant Human In Vitro Individual Integrins Knock-out Knockout Mice MYC Family Genes Malignant Neoplasms Malignant neoplasm of prostate Measures Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Neoplasms Oncogenes Oncogenic One-Step dentin bonding system PIK3CA gene PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Play Polyomavirus Property Protein Binding Protein Isoforms Proteomics Receptor Protein-Tyrosine Kinases Research Research Personnel Resistance Role Signal Transduction Solid Neoplasm T-Lymphocyte Time Tissues Toxic effect Tumor Cell Line Tumor Suppressor Genes Viral Tumor Antigens Work c-myc Genes cohort genetic regulatory protein in vivo inhibitor/antagonist insulin signaling interest pre-clinical public health relevance receptor coupling research study resistance mechanism tissue culture tool tumor tumor progression tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The PI3 Kinase pathway is a leading candidate for targeted tumor therapy at this time. This pathway is frequently activated via mutation in both commonly occurring and rare tumor types. Current PI3K directed therapies are targeted to the catalytic subunits of the so-called Class I enzymes. Of the four Class I isoforms, only p110beta and p110beta are expressed in all tissues. Both the p110beta and p110beta isoforms appear to play distinct roles in oncogenic transformation, and, interestingly, isoform functionality varies according to tumor type. Only p110beta is activated by mutations in human tumors. Experiments with conditional knockout mice and shRNAs in human tumor cell lines have shown that p110beta is the key isoform for signaling from oncogenic receptor tyrosine kinases as well as oncogenes such as ras or polyoma middle T antigen. Surprisingly p110beta has been shown to be key for tumors featuring Pten loss, though mechanistic understanding of this data has been lacking. The roles of the two isoforms in insulin signaling are also quite distinct, with p110beta carrying the larger part of the signal, suggesting that inhibiting individual isoforms could have fewer side-effects than the pan inhibitors now entering the clinic. Thus we are excited that the differences in the roles of the isoforms may be exploited to make safer second-generation drugs for PI3Ks. While pharma has concentrated on p110beta specific inhibitors, we have worked to develop a tool compound, Kin-193, that can be used to treat Pten null tumors in mice via inhibition of p110beta. In this grant we seek to understand the mechanism(s) by which p110beta is specifically activated in Pten null tumors, to characterize Kin-193's effects on human xenograft tumors in mice, and to determine how resistance to p110beta inhibitors may arise.

描述（由申请人提供）：PI3激酶途径是目前靶向肿瘤治疗的主要候选途径。在常见和罕见的肿瘤类型中，该途径经常通过突变而被激活。目前的 PI3K 定向疗法针对所谓的 I 类酶的催化亚基。在四种 I 类亚型中，只有 p110beta 和 p110beta 在所有组织中表达。 p110beta 和 p110beta 亚型似乎在致癌转化中发挥着不同的作用，有趣的是，亚型功能根据肿瘤类型而变化。只有 p110beta 会被人类肿瘤中的突变激活。对条件敲除小鼠和人类肿瘤细胞系中的 shRNA 进行的实验表明，p110beta 是致癌受体酪氨酸激酶以及 ras 或多瘤中 T 抗原等致癌基因信号传导的关键亚型。令人惊讶的是，p110beta 已被证明是 Pten 缺失肿瘤的关键，尽管对此数据的机制了解还缺乏。两种异构体在胰岛素信号传导中的作用也非常不同，p110beta 携带大部分信号，这表明抑制单个异构体可能比现在进入临床的泛抑制剂具有更少的副作用。因此，我们很高兴能够利用异构体作用的差异来制造更安全的第二代 PI3K 药物。虽然 Pharma 专注于 p110beta 特异性抑制剂，但我们致力于开发一种工具化合物 Kin-193，可通过抑制 p110beta 来治疗小鼠的 Pten 缺失肿瘤。在这笔资助中，我们试图了解 p110beta 在 Pten 缺失肿瘤中特异性激活的机制，以表征 Kin-193 对小鼠人类异种移植肿瘤的影响，并确定如何产生对 p110beta 抑制剂的耐药性。