Targeting the p110beta isoform of PI3 kinase in prostate cancer

 描述（由申请人提供）：肿瘤抑制磷酸酶和张力蛋白同源物（PTEN）（磷脂酰肌醇3-激酶（PI 3 K）活性的关键负调节因子）的缺失是原发性前列腺癌（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PI 3 K通路的过度活化在PCa的发病机制中起重要作用，并暗示PI 3 K是这种肿瘤类型中有吸引力的靶点。然而，PI 3 K抑制剂在多种癌症类型（包括PCa）中的早期临床试验令人失望。这些早期PI 3 K抑制剂（主要是阻断所有I类PI 3 K亚型作用的泛PI 3 K抑制剂）的临床疗效可能受到缺乏亚型特异性的限制。事实上，临床前工作和新兴的临床试验表明，个别亚型的抑制剂可能会实现更大的疗效，副作用更少。例如，Cal 101是PI 3 K的p110 d亚型的抑制剂，在某些B细胞恶性肿瘤中表现出显著的临床疗效。早期未发表的临床结果也表明，p110 a抑制剂在管腔型乳腺癌中优于泛PI 3 K抑制剂。由于编码p110 a的PIK 3CA基因在肿瘤中经常发生突变，因此p110 a引起了制药和基础研究人员的大量关注。然而，使用鼠遗传模型，我们确定p110 β是PTEN缺失的前列腺肿瘤的关键靶点。我们和其他人随后表明，人PTEN-null前列腺癌细胞系选择性依赖于p110 β。我们进一步鉴定了Kin-193，也称为AZD 6482，作为一种有效和特异性的p110抑制剂，适用于体外和小鼠研究。值得注意的是，一种新的p110抑制剂GSK 2636771目前正在PTEN缺陷型晚期实体瘤患者中进行临床试验（NCT 01458067）。因此，在临床前环境中仔细研究p110 β抑制剂是必要的和及时的。在这个gant中，我们建议在体外和体内使用人癌细胞系，遗传小鼠模型以及原发性人前列腺肿瘤外植体来评估这类新型抑制剂在前列腺癌中的治疗潜力，以开发预测对p110 β抑制反应的生物标志物，并确定用于基于p110 β的治疗的最佳组合伴侣药物。这项拨款中提出的研究可能会提供重要的信息，有助于优化 这类抑制剂在PTEN缺陷型肿瘤中的临床影响。

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 Early unpublished clinical results also suggest that p110a inhibitors are outperforming pan-PI3K inhibitors in luminal breast cancer.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