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：
9248261
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/9248261
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Adverse effects Androgen Receptor Androgens Architecture Attention B lymphoid malignancy B-Lymphocytes 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 Hour Human In Vitro Individual Malignant neoplasm of prostate Metastatic Prostate Cancer Methods Morphology Mouse Cell Line Mus Mutate Operative Surgical Procedures PIK3CA gene PTEN gene Pathogenesis Pathologic Pathway interactions Patients Pharmacologic Substance Play Prediction of Response to Therapy Prostate Prostatic Neoplasms Protein Isoforms Research Personnel Role S-Phase Fraction Sampling Slice Solid Neoplasm Specificity Staining method Stains System Testing Therapeutic Time Tissues Tumor Suppressor Proteins Work base cancer type castration resistant prostate cancer clinical candidate clinical efficacy deprivation experience in vivo inhibitor/antagonist interest kinase inhibitor malignant breast neoplasm men model design mouse model novel phosphoproteomics pre-clinical predicting response predictive marker prostate cancer cell line public health relevance 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.

描述（由适用提供）：肿瘤抑制磷酸酶和Tensin同源物（PTEN）的丧失，这是磷脂酰肌醇3-激酶（PI3K）活性的关键负调节剂，是原发性前列腺癌（PCA）中最常见的遗传事件之一。此外，它的频率进一步增加了转移性PCA的频率，表明PI3K途径的过度激活在PCA和隐式PI3K的发病机理中起着重要作用，作为该肿瘤类型的有吸引力的靶标。但是，包括PCA在内的多种癌症类型的PI3K抑制剂的早期临床试验令人失望。这些早期PI3K抑制剂的临床效率在很大程度上是PAN-PI3K抑制剂，这些抑制剂阻断了所有I类PI3K同工型的作用，可能受其缺乏同工型特异性的限制。实际上，临床前的工作和新兴的临床试验表明，单个同工型的抑制剂可能会获得更大的有效性，而副作用较小。例如，PI3K的P110D同工型抑制剂Cal101在某些B细胞恶性肿瘤中表现出显着的临床效率。早期未发表的临床结果还表明，p110a抑制剂在腔内乳腺癌中的表现优于PAN-PI3K抑制剂。由于编码p110a的PIK3CA基因在肿瘤中经常突变，因此P110a吸引了大部分注意力。来自药品和基础研究人员。但是，使用鼠遗传模型，我们将p110ß确定为PTEN-NULL前列腺肿瘤中的关键靶标。我们和其他人随后表明，人类PTEN-NULL前列腺癌细胞系有选择性地取决于P110ß。我们进一步确定了Kin-193，也称为AZD6482，是一种适合体外和小鼠研究的潜在和特定的P110ß抑制剂。值得注意的是，新的P110ß抑制剂GSK2636771现在正在临床试验中，患有缺乏PTEN的晚期实体瘤患者（NCT01458067）。因此，仔细研究临床前环境中的p110ß抑制剂既需要及时。在这种甘特中，我们建议使用人类癌细胞系，遗传小鼠模型以及原发性人类前列腺肿瘤外植体，评估这种新型的前列腺癌和体内抑制剂的治疗潜力，以预测对P110ß抑制作用的反应，并确定对P110USPAIPTION的最佳组合伴侣的反应。本赠款中提出的研究可能会提供重要信息，以帮助优化这类抑制剂在缺乏PTEN的肿瘤中的临床影响。