Signal Transduction Inhibitor Therapy for Lymphoma

非霍奇金淋巴瘤(NHL)和霍奇金病(HD)的治疗进展 几十年来，这些常见恶性肿瘤患者的存活率有所提高。然而，近40%的 大细胞非霍奇金淋巴瘤患者、80%的惰性非霍奇金淋巴瘤患者和20%的HD患者没有治愈并死于他们的疾病。 显然，具有基于信号转导知识的独特作用机制的新药物 淋巴瘤细胞中的通路是推进淋巴瘤治疗所必需的。这项提案的重点是 淋巴瘤细胞中的磷脂酰肌醇-3激酶(PI3K)和Raf激酶通路。我们已经证明了 使用PI3K通路抑制剂(替西罗莫司/伊维洛莫斯)治疗NHL/HD患者的单药活性 和法尼基转移酶抑制剂(替法尼布)。初步体外研究表明Raf具有活性 激酶/VGFR抑制剂索拉非尼对淋巴瘤细胞的作用与PI3K途径抑制剂具有协同作用。 这项建议的总体假设是，化疗药物与一种或多种 信号转导抑制剂(STI)将提高NHL/HD患者的缓解率和生存率。至 验证这一假设，该项目包括临床试验，评估性传播感染的合理组合 其他和与常规化疗药物一起，患者淋巴瘤细胞中的研究生物标志物 参与这些试验，以及在原发肿瘤细胞中进行新药物和组合的体外研究，这些研究将 引领下一代临床试验。这项工作有三个具体目标。 目的1、探讨PI3K/Akt/mTOR途径抑制剂与Raf-TOR联合应用的安全性和有效性。 激酶抑制剂和常规化疗药物 目的2，评估性传播感染组合在靶通路上的作用，并确定潜在的标记物 使用来自AIM 1试验患者的恶性B细胞的抗肿瘤效果 目的3，研究含有针对PI3K/Akt/mTOR途径和其他途径的药物的新组合 STIS或常规药物在体外对恶性B细胞的作用为下一代STI提供理论基础 临床试验。我们的初步研究将集中在靶向PI3K/Akt/mTOR途径组件或那些 已知的与PI3K/Akt/mTOR通路相连的通路。具有大量临床应用的组合 然后，活动将转移到NCCTG或ECOG等合作小组的大规模测试中。 LAY语言声明：淋巴瘤细胞对从外部传递到细胞的信号做出反应 在细胞内，导致细胞生长。这个项目的重点是治疗淋巴瘤患者的新药 干扰那些信号。对其中几种药物的初步研究是有希望的，目标是 该项目将把这些药物结合在一起，并与其他常见的化疗药物结合起来，以促进 淋巴瘤的治疗。

Treatment advances for non-Hodgkin Lymphoma (NHL) and Hodgkin Disease (HD) over the last several decades have improved the survival of patients with these common malignancies. However, nearly 40% of patients with large cell NHL, 80% with indolent NHL, and 20% with HD are not cured and die of their disease. It is clear that new agents with unique mechanisms of action based on knowledge of signal transduction pathways in lymphoma cells are needed to advance lymphoma treatment. This proposal focuses on the phosphatidylinositol-3 kinase (PI3K) and Raf kinase pathways in lymphoma cells. We have demonstrated single agent activity in patients with NHL/HD using inhibitors of the PI3K pathway (temsirolimus/everolimus) and inhibitors of farnesyl transferase (tipifarnib). Preliminary in vitro studies demonstrate activity of the Raf kinase/VGFR inhibitor sorafenib against lymphoma cells that is synergistic with the PI3K pathway inhibitors. The overall hypothesis of this proposal is that a combination of chemotherapy agents with one or more of the signal transduction inhibitors (STIs) will improve the response rate and survival of patients with NHL/HD. To test this hypothesis, this project includes clinical trials that assess rational combinations of STIs with each other and with conventional chemotherapy agents, investigational biomarkers in lymphoma cells from patients participating in these trials, and in vitro studies of new agents and combinations in primary tumor cells that will lead to the next generation of clinical trials. This work is organized in 3 specific aims. Aim 1, to investigate the safety and efficacy of PI3K/Akt/mTOR pathway inhibitors in combination with Raf- kinase inhibitors and conventional chemotherapy agents Aim 2, to assess the action of combinations of STIs on the targeted pathways and identify potential markers of anti-tumor efficacy using malignant B-cells from patients entered on the trials in Aim 1 Aim 3, to investigate novel combinations containing agents targeting the PI3K/Akt/mTOR pathway and other STIs or conventional agents in malignant B-cells in vitro to provide the rationale for the next generation of clinical trials. Our initial studies will focus on drugs that target PI3K/Akt/mTOR pathway components or those of pathways known to connect with the PI3K/Akt/mTOR pathway. Combinations with substantial clinical activity will then move to large-scale testing in the cooperative groups such as NCCTG or ECOG. Lay Language Statement: Lymphoma cells respond to signals that are transmitted from the outside to the inside of the cell resulting in cell growth. This project focuses on new drugs for patients with lymphoma that interfere with those signals. Preliminary studies with several of these drugs are promising and the goal of this project will be to combine these agents together and with other common chemotherapy agents to advance the treatment of lymphoma.