Targeting the p110beta Isoform of PI3 Kinase in Pten Null Tumors

描述(由申请人提供)：PI3Kinase通路是目前靶向肿瘤治疗的主要候选者。在常见和罕见的肿瘤类型中，这一途径经常通过突变被激活。目前的PI3K导向疗法针对的是所谓的第I类酶的催化亚单位。在四种I类异构体中，只有p110β和p110β在所有组织中表达。P110β和p110β亚型似乎都在致癌转化中扮演着不同的角色，有趣的是，异构体的功能因肿瘤类型而异。在人类肿瘤中，只有p110β被突变所激活。用条件性基因敲除小鼠和人类肿瘤细胞系中的shRNAs进行的实验表明，p110β是癌基因受体酪氨酸激酶以及ras或多瘤中T抗原等癌基因信号的关键异构体。令人惊讶的是，p110β被证明是以Pten缺失为特征的肿瘤的关键，尽管对这一数据缺乏机制理解。这两种异构体在胰岛素信号中的作用也相当不同，p110β携带了信号的大部分，这表明抑制单独的异构体可能比目前进入临床的PAN抑制剂有更少的副作用。因此，我们感到兴奋的是，异构体作用的差异可能被利用来制造更安全的PI3K第二代药物。虽然制药公司一直专注于p110β特异性抑制剂，但我们已经努力开发了一种工具化合物Kin-193，可以通过抑制p110β来治疗小鼠的Pten零肿瘤。在这项资助中，我们试图了解p110β在Pten缺失肿瘤中被特异性激活的机制(S)，表征Kin-193‘S对小鼠人异种移植瘤的影响，并确定如何产生对p110β抑制剂的耐药性。

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.