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.

描述（由申请人提供）：肿瘤抑制磷酸酶和张力蛋白同源物 (PTEN) 的丧失（PTEN）是磷脂酰肌醇 3-激酶 (PI3K) 活性的关键负调节因子，是原发性前列腺癌 (PCa) 中最常见的遗传事件之一。此外，其频率在转移性PCa中进一步增加，表明PI3K通路的过度激活在PCa和PCa的发病机制中起着重要作用。然而，PI3K 抑制剂在多种癌症类型（包括 PCa）中的早期临床试验结果令人失望，这些早期 PI3K 抑制剂主要是阻断 PCA 的泛 PI3K 抑制剂。事实上，所有 I 类 PI3K 同工型的作用可能因其缺乏同工型特异性而受到限制。事实上，临床前工作和新出现的临床试验表明，个别同工型的抑制剂可能会受到限制。例如，Cal101（PI3K p110d 亚型的抑制剂）在某些 B 细胞恶性肿瘤中表现出显着的临床疗效，也表明 p110a 抑制剂在治疗中优于泛 PI3K 抑制剂。由于编码 p110a 的 PIK3CA 基因在肿瘤中经常发生突变，因此 p110a 引起了人们的广泛关注。然而，我们使用小鼠遗传模型确定了 p110ß 是 PTEN 缺失的前列腺肿瘤的关键靶标，我们和其他人随后表明，人类 PTEN 缺失的前列腺癌细胞系选择性依赖于 p110ß。进一步鉴定出 Kin-193（也称为 AZD6482）是一种有效且特异性的 p110ß 抑制剂，适用于体外和小鼠研究。值得注意的是，这是一种新的 p110ß。抑制剂 GSK2636771 现已在 PTEN 缺陷的晚期实体瘤患者中进行临床试验 (NCT01458067) 因此，在临床前环境中仔细研究 p110ß 抑制剂是必要且及时的。在本甘特试验中，我们建议评估其治疗潜力。此类新型前列腺癌抑制剂在体外和体内使用人类癌细胞系、遗传小鼠模型以及原代人类前列腺肿瘤外植体来开发生物标志物预测对 p110ß 抑制的反应，并确定基于 p110ß 的治疗的最佳组合药物。本次资助中提出的研究可能会提供有助于优化的重要信息。此类抑制剂对 PTEN 缺陷肿瘤的临床影响。