Targeting the p110beta isoform of PI3 kinase in prostate cancer

 描述(由申请人提供)：肿瘤抑制因子磷酸酶和紧张素同源基因(PTEN)的缺失是原发性前列腺癌(PCa)最常见的遗传事件之一。PTEN是磷脂酰肌醇3-激酶(PI3K)活性的关键负面调节因子。此外，PI3K在转移性前列腺癌中的频率进一步增加，表明PI3K通路的过度激活在PCa的发病机制中起着重要作用，并提示PI3K是该肿瘤的一个有吸引力的靶点。然而，PI3K抑制剂在包括前列腺癌在内的多种癌症类型中的早期临床试验一直令人失望。这些早期的PI3K抑制剂主要是PAN-PI3K抑制剂，可以阻断所有I类PI3K亚型的作用，其临床疗效可能因缺乏异构体特异性而受到限制。事实上，临床前工作和新出现的临床试验表明，个别异构体的抑制剂可能取得更大的疗效和更少的副作用。例如，Cal101是PI3K的p110d亚型的抑制剂，在某些B细胞恶性肿瘤中显示出显著的临床疗效。早期未发表的临床结果也表明，p110a抑制剂在管腔乳腺癌中的疗效优于泛PI3K抑制剂。由于编码p110a的PIK3CA基因在肿瘤中经常发生突变，p110a引起了制药和基础研究人员的大部分关注。然而，使用小鼠遗传模型，我们发现p110ü是PTEN缺失的前列腺癌的关键靶点。我们和其他人随后表明，人PTEN缺失的前列腺癌细胞系选择性地依赖于p110？我们进一步确定Kin-193，也被称为AZD6482，是一种有效和特异的p110？抑制剂，适用于体外和小鼠的研究。值得注意的是，一种新的p110ü抑制剂GSK2636771现在正在对PTEN缺陷的晚期实体肿瘤患者(NCT01458067)进行临床试验。因此，认真研究临床前环境中的p110？抑制剂是必要和及时的。在这项研究中，我们建议使用人类癌细胞系、遗传小鼠模型以及原代人类前列腺癌外植体，在体外和体内评估这种新型抑制剂在前列腺癌中的治疗潜力，开发预测对p110？抑制的反应的生物标记物，并为基于p110？的治疗确定最佳的合作伙伴药物。这笔拨款中提议的研究可能会提供重要的信息，有助于优化 这类抑制物对PTEN缺陷性肿瘤的临床影响。

 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 Early unpublished clinical results also suggest that p110a inhibitors are outperforming pan-PI3K inhibitors in luminal breast cancer.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.