Cell Survival Pathways and Inhibitors in Leukemia

描述（由申请方提供）：肿瘤特征性表现为 增强细胞增殖和存活的突变。两个公认的 细胞存活途径是RAF到MEK到ERK和PI 3-激酶到Akt。许多 这些途径的抑制剂现在处于临床试验或早期阶段， 发展然而，早期的结果表明，这些抑制剂更有可能 抑制生长而不是杀死肿瘤细胞。我们最近的观察表明， 这表明，这种抑制剂在联合使用时可能更有价值 与传统的抗癌药物。具体而言，已经表明， MEK抑制剂可显著提高细胞凋亡率， 长春碱在髓系白血病ML-1细胞和HL 6 O细胞中的作用。U937细胞 对MEK抑制剂不敏感，但对长春碱敏感， PI 3-激酶抑制剂。这些观察结果导致了这样的假设， 不同的白血病优先使用不同的存活信号传导途径， 通过确定特定白血病使用的途径， 组合可以针对该患者个体化。这个项目的目标 是研究新鲜分离的人类白血病细胞， 这两种细胞的抑制剂使它们对化疗敏感 生存之路。具体目标是测定白血病细胞的 ERK和Akt的磷酸化作为所用信号传导途径的指标， 并将这些信号传导途径的联合收割机抑制剂与长春花生物碱 体内测定细胞凋亡诱导率。另外的实验 将决定正常的白细胞祖细胞，没有一个 癌基因增强的细胞存活途径，对这些药物有抗药性 组合，从而表明这样的疗法对于肿瘤可能是选择性的。 最后，将在白血病中检测Jun N-末端激酶（JNK）的活化 接受长春新碱治疗的患者，以确认该途径 在患者耐受的药物浓度下激活。JNK的激活 细胞凋亡抑制剂诱导的增强的细胞凋亡是必需的， Erk和Akt通路。成功完成这些目标将确定 白血病患者可能受益于这些抑制剂的施用， 信号通路，并促进临床试验的设计，以测试其 与其它抗癌剂组合的功效。

DESCRIPTION (provided by applicant): Tumors characteristically exhibit mutations that enhance cell proliferation and survival. Two well-recognized cell survival pathways are RAF to MEK to ERK and PI3-kinase to Akt. Many inhibitors of these pathways are now in clinical trials or at earlier stages of development. However, early results suggest these inhibitors are more likely to suppress growth than kill the tumor cells. Our recent observations have demonstrated that such inhibitors may be more valuable when used in combination with more traditional anticancer agents. Specifically, it has been shown that a MEK inhibitor can dramatically enhance the rate of apoptosis induced by vinblastine in myeloid leukemia ML-1 cells and HL6O cells. However, U937 cells are insensitive to the MEK inhibitor but are sensitized to vinblastine by an inhibitor of PI3-kinase. These observations have led to the hypothesis that different leukemias preferentially use different survival signaling pathways, and that by defining which pathway a specific leukemia uses, effective drug combinations can be individualized for that patient. The goal of this project is to study freshly-isolated human leukemia cells and define the frequency with which they are sensitized to chemotherapy by inhibitors of these two cell survival pathways. The specific aims are to assay leukemia cells for phosphorylation of ERK and Akt as indicators of the signaling pathways used, and to combine inhibitors of these signaling pathways with vinca alkaloids ex vivo to determine the rate of induction of apoptosis. Additional experiments will determine whether normal leukocyte progenitors, which do not have an oncogene-enhanced cell survival pathway, are resistant to these drug combinations thereby suggesting such a therapy may be selective for the tumor. Finally, activation of Jun N-terminal kinase (JNK) will be assayed in leukemia patients receiving vincristine therapy, to confirm that this pathway is activated at drug concentrations tolerated by patients. Activation of the JNK pathway is necessary for the enhanced apoptosis induced by inhibitors of the Erk and Akt pathways. Successful completion of these aims will identify which leukemia patients might benefit from administration of inhibitors of these signaling pathways, and facilitate the design of clinical trials to test their efficacy in combination with other anticancer agents.