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：
8986642
负责人：
Jean Zhao
金额：
$ 41.36万
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 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8986642
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Adverse effects Attention Automobile Driving B-Lymphocytes Binding Proteins Blood Glucose Canis familiaris Catalytic Domain Cause of Death Clinic Clinical Trials Communities Coupled Data Enzymes Exhibits Funding Generations Genes Genetic Genetic Engineering Genetic Models Goals Grant Health Human In Vitro Individual Integrins Knock-out Knockout Mice 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 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 receptor coupling research study resistance mechanism targeted treatment 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激酶途径目前是靶向肿瘤疗法的领先候选者。该途径经常通过突变激活，在常见的肿瘤类型和罕见的肿瘤类型中。当前的PI3K定向疗法针对所谓的I类酶的催化亚基。在四个I类同工型中，只有P110BETA和P110BETA在所有组织中表达。 P110BETA和P110BETA同工型似乎在致癌转化中起着不同的作用，有趣的是，同工型功能根据肿瘤类型而变化。仅通过人类肿瘤突变激活P110Beta。在人类肿瘤细胞系中对条件敲除小鼠和shRNA进行的实验表明，P110BETA是来自致癌受体酪氨酸激酶以及诸如RAS或多瘤中间T抗原等癌基因的信号传导的关键同工型。令人惊讶的是，尽管缺乏对这些数据的机械理解，但P110BETA已被证明是具有PTEN损失的肿瘤的关键。两种同工型在胰岛素信号传导中的作用也很明显，其中P110BETA带有较大的信号，这表明抑制个体同工型的副作用可能比现在进入诊所的PAN抑制剂更少。因此，我们很兴奋，可以利用同工型的作用差异，以使PI3KS更安全的第二代药物。尽管Pharma集中在P110BETA特异性抑制剂上，但我们一直致力于开发一种工具化合物Kin-193，可通过抑制P110Beta来用于治疗小鼠中PTEN无效的肿瘤。在这笔赠款中，我们试图了解P1110BETA在PTEN NULL肿瘤中专门激活的机制，以表征Kin-193对小鼠人类异种移植肿瘤的影响，并确定对P110BETA抑制剂的抗性。