Targeting non-classical oncogenes as therapy for T-ALL

描述（由申请人提供）： T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血液系统癌症，发生于儿童和成人。尽管进行了强化治疗，但25%的儿童和青少年以及50%的T-ALL成人最终会死于这种疾病。此外，癌症治疗的晚期效应，包括永久性器官损伤、激素和生殖功能障碍以及第二种癌症，是儿童特别关注的问题，因为目前的治疗不加区别地针对所有分裂细胞。该提案的目标是确定和治疗靶向T-ALL生长和存活所必需的途径，其抑制毒性比标准化疗低得多。据报道，I类磷酸肌醇3-激酶（PI 3 K）/Akt信号通路在超过40%的T-ALL病例中被激活。虽然四种不同的I类PI 3 K亚型可能参与T-ALL发病机制，但没有一种参与这一过程。使用基因改变的动物和新型小分子抑制剂，我们已经确定了似乎对T- ALL的发展和生存至关重要的特定亚型。基于这些观察结果，我们建议有可能利用这种血液恶性肿瘤对这些特定PI 3 K亚型的“成瘾”作为T-ALL的新治疗途径。为了实现这些目标，我们提出了以下具体目标：目标1。确定2种新型亚型特异性PI 3 K抑制剂可能影响T-ALL发病机制的疗效和作用机制。这将通过评价这些抑制剂在PTEN缺失T-ALL动物模型、人T-ALL细胞系和原代患者样本中的作用来实现。重点将放在询问下游途径，调节细胞周期的进展，蛋白质合成和细胞存活使用生物化学和遗传学的方法相结合。目标2.揭示可能导致继发性耐药的潜在PI 3 K依赖性和非依赖性机制。这包括在动物中使用药物结合、化学诱导诱变和药物诱导耐药疾病的计算机模拟模型鉴定赋予耐药的点突变和替代信号传导途径。将进行生化和遗传分析，后者包括基因表达微阵列和基于阵列的比较基因组杂交。目标3.确定亚型特异性PI 3 K抑制剂对人T细胞的发育、外周扩增、存活和功能的影响。这将通过在独特的人胸腺/CD 34+干细胞异种移植模型中评价药物作用来实现。

DESCRIPTION (provided by applicant): T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer that occurs in children as well as adults. Despite intensive therapies, 25% of children and adolescents and 50% of adults with T-ALL will ultimately succumb to the disease. Moreover, the late effects of cancer treatment, including permanent organ damage, hormonal and reproductive dysfunction, and second cancers are a special concern in children as current therapies indiscriminately target all dividing cells. The goal of this proposal is to identify and therapeutically target a pathway that is essential for the growth and survival of T-ALL, the inhibition of which will be considerably less toxic than standard chemotherapy. Class I phosphoinositide 3-kinase (PI3K)/Akt signaling pathway has been reported to be activated in over 40% of cases of T-ALL. Although four distinct class I PI3K isoforms could participate in T-ALL pathogenesis, none have been implicated in this process. Using genetically altered animals and novel small molecule inhibitors, we have identified specific isoforms that appear to be essential for the development and survival of T- ALL. Based on these observations, we propose that it is possible to exploit the "addiction" of this hematological malignancy to these particular PI3K isoforms as a new therapeutic avenue for T-ALL. To achieve these objectives, we propose the following specific aims: Aim 1. To determine the efficacy and to define the mechanism(s) of action by which 2 novel isoform specific PI3K inhibitors may impact on T-ALL pathogenesis. This will be accomplished by evaluating the effects of these inhibitors in an animal model of PTEN null T-ALL, on human T-ALL cell lines, and on primary patient samples. Emphasis will be placed on interrogating downstream pathways that regulate cell cycle progression, protein synthesis, and cell survival using a combination of biochemical and genetic approaches. Aim 2. To uncover potential PI3K-dependent and independent mechanisms that may result in secondary resistance. This includes identifying resistance-conferring point mutations and alternative signaling pathways using in silico models of drug binding, chemical-induced mutagenesis, and drug-induced resistant disease in animals. Biochemical and genetic analyses will be performed, the latter including gene expression microarrays and array-based comparative genomic hybridization. Aim 3. To determine the effects of isoform specific PI3K inhibitors on the development, peripheral expansion, survival and function of human T cells. This will be accomplished by evaluating drug effects in a unique human thymus/CD34+ stem cell xenograft model.