Targeting the p110beta Isoform of PI3 Kinase in Pten Null Tumors

描述（由申请人提供）：PI 3激酶通路是目前靶向肿瘤治疗的主要候选者。该途径在常见和罕见肿瘤类型中经常通过突变激活。目前的PI 3 K定向疗法靶向所谓的I类酶的催化亚基。在四种I类亚型中，只有p110 β和p110 β在所有组织中表达。p110 β和p110 β亚型似乎在致癌转化中发挥不同的作用，有趣的是，亚型功能根据肿瘤类型而变化。只有p110 β被人类肿瘤中的突变激活。在人类肿瘤细胞系中使用条件性敲除小鼠和shRNA的实验表明，p110 β是致癌受体酪氨酸激酶以及癌基因（如ras或多瘤中间T抗原）信号传导的关键同种型。令人惊讶的是，p110 β已被证明是Pten丢失的肿瘤的关键，尽管缺乏对该数据的机制理解。这两种异构体在胰岛素信号传导中的作用也相当不同，p110 β携带大部分信号，这表明抑制单个异构体的副作用可能比现在进入临床的泛抑制剂更少。因此，我们很高兴可以利用亚型作用的差异来制造更安全的第二代PI 3 Ks药物。虽然制药公司专注于p110 β特异性抑制剂，但我们一直致力于开发一种工具化合物Kin-193，可用于通过抑制p110 β来治疗小鼠中的Pten无效肿瘤。在这项授权中，我们试图了解Pten无效肿瘤中p110 β特异性激活的机制，以表征Kin-193对小鼠人类异种移植肿瘤的作用，并确定对p110 β抑制剂的耐药性如何产生。

DESCRIPTION (provided by applicant): The PI3 Kinase pathway is a leading candidate for targeted tumor therapy at this time. This pathway is frequently activated via mutation in both commonly occurring and rare tumor types. Current PI3K directed therapies are targeted to the catalytic subunits of the so-called Class I enzymes. Of the four Class I isoforms, only p110beta and p110beta are expressed in all tissues. Both the p110beta and p110beta isoforms appear to play distinct roles in oncogenic transformation, and, interestingly, isoform functionality varies according to tumor type. Only p110beta is activated by mutations in human tumors. Experiments with conditional knockout mice and shRNAs in human tumor cell lines have shown that p110beta is the key isoform for signaling from oncogenic receptor tyrosine kinases as well as oncogenes such as ras or polyoma middle T antigen. Surprisingly p110beta has been shown to be key for tumors featuring Pten loss, though mechanistic understanding of this data has been lacking. The roles of the two isoforms in insulin signaling are also quite distinct, with p110beta carrying the larger part of the signal, suggesting that inhibiting individual isoforms could have fewer side-effects than the pan inhibitors now entering the clinic. Thus we are excited that the differences in the roles of the isoforms may be exploited to make safer second-generation drugs for PI3Ks. While pharma has concentrated on p110beta specific inhibitors, we have worked to develop a tool compound, Kin-193, that can be used to treat Pten null tumors in mice via inhibition of p110beta. In this grant we seek to understand the mechanism(s) by which p110beta is specifically activated in Pten null tumors, to characterize Kin-193's effects on human xenograft tumors in mice, and to determine how resistance to p110beta inhibitors may arise.