Signal transduction inhibitor therapy for Lymphoma

描述（由申请人提供）：在过去几十年中，非霍奇金淋巴瘤（NHL）和霍奇金病（HD）的治疗进展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%的惰性NHL患者和20%的HD患者未能治愈并死于疾病。很明显，需要基于淋巴瘤细胞中信号转导途径的知识的具有独特作用机制的新药剂来推进淋巴瘤治疗。该提案集中于淋巴瘤细胞中的磷脂酰肌醇-3激酶（PI 3 K）和Raf激酶通路。我们已经证明了使用PI 3 K通路抑制剂（替西罗莫司/依维莫司）和法尼基转移酶抑制剂（替吡法尼）在NHL/HD患者中的单药活性。初步体外研究证明Raf激酶/VGFR抑制剂索拉非尼对淋巴瘤细胞的活性与PI 3 K途径抑制剂协同。该建议的总体假设是，化疗药物与一种或多种信号转导抑制剂（STI）的组合将提高NHL/HD患者的缓解率和生存率。为了验证这一假设，该项目包括临床试验，评估STI相互之间以及与常规化疗药物的合理组合，参与这些试验的患者淋巴瘤细胞中的研究性生物标志物，以及将导致下一代临床试验的新药物和原发性肿瘤细胞组合的体外研究。本工作有3个具体目的：目的1，研究PI 3 K/Akt/mTOR通路抑制剂与Raf激酶抑制剂和常规化疗药物联合使用的安全性和有效性。目的2，评估STI组合对靶向通路的作用，并使用来自目的1中进入试验的患者的恶性B细胞鉴定抗肿瘤疗效的潜在标志物。目的3，在体外研究含有靶向PI 3 K/Akt/mTOR通路的药物和其他STI或常规药物的新型组合，为下一代临床试验提供理论基础。我们的初步研究将集中在靶向PI 3 K/Akt/mTOR通路组分或已知与PI 3 K/Akt/mTOR通路相关的通路组分的药物上。具有实质性临床活性的组合随后将在合作组（如NCCTG或ECOG）中进行大规模测试。外行语言声明：淋巴瘤细胞响应从外部传输到细胞内部导致细胞生长的信号。该项目的重点是干扰这些信号的淋巴瘤患者的新药。这些药物的初步研究是有希望的，该项目的目标是将这些药物与其他常见的化疗药物一起联合收割机，以促进淋巴瘤的治疗。

DESCRIPTION (provided by applicant): 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.