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Targeting the p110beta isoform of PI3 kinase in prostate cancer

靶向前列腺癌中 PI3 激酶的 p110beta 亚型

基本信息

批准号：
9036357
负责人：
Massimo Loda
金额：
$ 55.41万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9036357
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Adverse effects Androgen Receptor Androgens Architecture Attention B lymphoid malignancy B-Lymphocytes Biological Markers Biological Preservation Blood Glucose Cancer cell line Cell Line Clinical Clinical Trials Collection Combined Modality Therapy Complement Engineering Event Excision Freezing Frequencies Gene Chips Genetic Genetic Engineering Genetic Models Grant Growth Harvest Health Hour Human In Vitro Individual Malignant neoplasm of prostate Metastatic Prostate Cancer Methods Mouse Cell Line Mus Mutate Operative Surgical Procedures PIK3CA gene PTEN gene Pathogenesis Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Play Prostate Prostatic Neoplasms Protein Isoforms Research Personnel Role Sampling Slice Solid Neoplasm Specificity Staining method Stains System Testing Therapeutic Tissues Tumor Suppressor Proteins Work base cancer type castration resistant prostate cancer clinical efficacy deprivation experience in vivo indexing inhibitor/antagonist interest kinase inhibitor malignant breast neoplasm men model design mouse model novel phosphoproteomics pre-clinical predicting response prostate cancer cell line response targeted treatment tumor

项目摘要

DESCRIPTION (provided by applicant): Loss of the tumor suppressor phosphatase and tensin homolog (PTEN), the key negative regulator of Phosphatidylinositol 3-Kinase (PI3K) activity, is one of the most common genetic events in primary prostate cancer (PCa). Moreover, its frequency further increases in metastatic PCa, indicating that hyperactivation of the PI3K pathway plays an important role in the pathogenesis of PCa and implicating PI3K as an attractive target in this tumor type. However, early clinical trials with PI3K inhibitors in multipe cancer types, including PCa, have been disappointing. The clinical efficacy of these early PI3K inhibitors, which were largely pan-PI3K inhibitors that block the action of all Class I PI3K isoforms, may have been limited by their lack of isoform specificity. Indeed, preclinical work and emerging clinical trials suggest that inhibitors of individual isoforms may achieve greater efficac with fewer side effects. For example, Cal101, an inhibitor of the p110d isoform of PI3K, has demonstrated remarkable clinical efficacy in certain B-cell malignancies. Early unpublished clinical results also suggest that p110a inhibitors are outperforming pan-PI3K inhibitors in luminal breast cancer. Because the PIK3CA gene encoding p110a is frequently mutated in tumors, p110a has garnered the bulk of the attention from pharmaceutical and basic researchers. However, using a murine genetic model we identified p110ß as a key target in PTEN-null prostate tumors. We and others have subsequently shown that human PTEN-null prostate cancer cell lines are selectively dependent on p110ß. We have further identified Kin-193, also known as AZD6482, as a potent and specific p110ß inhibitor suitable for studies in vitro and in mice. Notably, a new p110ß inhibitor, GSK2636771, is now in clinical trials in patients with PTEN-deficient advanced solid tumors (NCT01458067). Therefore, it is both imperative and timely to carefully investigate p110ß inhibitors in preclinical settings. In this gant we propose to evaluate the therapeutic potential of this novel class of inhibitors in prostate cancer in vitro and in vivo using human cancer cell lines, genetic mouse models as well as primary human prostate tumor explants, to develop biomarkers predictive of response to p110ß inhibition, and to identify optimal combination partner agents for p110ß-based therapy. The studies proposed in this grant will likely provide important information that will help to optimize the clinical impact of this class of inhibitors in PTEN-deficient tumors.