P2 - 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，在过去的几年中， 几十年来，已经改善了这些常见恶性肿瘤患者的生存率。然而，近40%的 大细胞NHL患者、80%惰性NHL患者和20% HD患者不能治愈并死于其疾病。 很明显，基于信号转导的知识，具有独特作用机制的新药剂 需要淋巴瘤细胞中的通路来推进淋巴瘤治疗。该提案的重点是 磷脂酰肌醇-3激酶（PI 3 K）和Raf激酶途径。我们已经证明 使用PI 3 K通路抑制剂（替西罗莫司/依维莫司）在NHL/HD患者中的单药活性 和法尼基转移酶抑制剂（替吡法尼）。初步的体外研究证明了Raf的活性 激酶/VGFR抑制剂索拉非尼对淋巴瘤细胞的作用，其与PI 3 K通路抑制剂协同。 该提议的总体假设是化疗剂与一种或多种化疗药物的组合是有效的。 信号转导抑制剂（STI）将改善NHL/HD患者的缓解率和生存率。到 为了验证这一假设，该项目包括临床试验，评估STI与每种STI的合理组合， 其他和常规化疗药物，患者淋巴瘤细胞中的研究性生物标志物 参与这些试验，以及在原发性肿瘤细胞中进行的新药物和组合的体外研究， 引领下一代的临床试验这项工作有三个具体目标。 目的1，研究PI 3 K/Akt/mTOR通路抑制剂与Raf-1联合应用的安全性和有效性。 激酶抑制剂和常规化疗剂 目的2，评估STI组合对靶向通路的作用，并确定潜在的 使用来自目标1中进入试验的患者的恶性B细胞的抗肿瘤功效 目的3，研究含有靶向PI 3 K/Akt/mTOR通路的药剂和其他靶向药物的新组合， STI或常规药物在体外恶性B细胞中的作用，为下一代 临床试验我们的初步研究将集中在靶向PI 3 K/Akt/mTOR通路组分的药物或那些 已知与PI 3 K/Akt/mTOR通路相关的通路。与实质性临床 然后，活动将转移到合作组（如NCCTG或ECOG）中的大规模测试。 外行语言声明：淋巴瘤细胞响应信号是从外面传送到 导致细胞生长。该项目的重点是针对淋巴瘤患者的新药， 干扰这些信号。这些药物中的几种的初步研究是有希望的， 该项目将是将这些药物与其他常用化疗药物一起联合收割机，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.