Signal transduction inhibitor therapy for Lymphoma

淋巴瘤的信号转导抑制剂治疗

• 批准号: 7676766
• 负责人: Thomas E. Witzig
• 金额: $ 33.66万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676766
• 关键词: 1-Phosphatidylinositol 3-Kinase; Apoptosis; B lymphoid malignancy; B-Lymphocytes; BAY 54-9085; Biological Markers; Cell Line; Cell Proliferation; Cell physiology; Cells; Clinical; Clinical Trials; Combination Drug Therapy; Common Neoplasm; Conduct Clinical Trials; Development; Disease; Drug Delivery Systems; Eastern Cooperative Oncology Group; Etoposide; Farnesyl Transferase Inhibitor; Future; Goals; Hematology; Hodgkin Disease; In Vitro; Indolent; Investigation; Knowledge; Language; Lead; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mantle Cell Lymphoma; Mayo Clinic Cancer Center; Multiple Myeloma; New Agents; Non-Hodgkin' s Lymphoma; North Central Cancer Treatment Group; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I/II Trial; Phase II Clinical Trials; Phosphotransferases; Primary Neoplasm; Proteins; Proto-Oncogene Proteins c-akt; Radioimmunoconjugate; Raf Kinase Inhibitor; Receptor Protein-Tyrosine Kinases; Regulation; Relapse; Research; Research Personnel; Resources; SDZ RAD; Safety; Sampling; Scientist; Signal Pathway; Signal Transduction; Signal Transduction Inhibitor; Signal Transduction Pathway; Sirolimus; Stem cell transplant; Survival Rate; Testing; Time; Tipifarnib; Tissue Sample; Tumor Angiogenesis; United States; Vascular Endothelial Growth Factor Receptor; Work; Zarnestra; base; cell growth; chemotherapy; improved; inhibitor/antagonist; mTOR protein; member; neoplastic cell; next generation; novel; programs; raf Kinases; response; rituximab; tumor

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.

描述(由申请人提供)：在过去的几十年里，非霍奇金淋巴瘤(NHL)和霍奇金病(HD)的治疗进展提高了这些常见恶性肿瘤患者的存活率。然而，近40%的大细胞NHL患者、80%的惰性NHL患者和20%的HD患者没有治愈并死于他们的疾病。显然，基于对淋巴瘤细胞信号转导途径的了解，需要具有独特作用机制的新的药物来促进淋巴瘤的治疗。这项建议集中在淋巴瘤细胞中的磷脂酰肌醇-3激酶(PI3K)和Raf激酶通路。我们使用PI3K途径的抑制剂(替西罗莫司/伊维洛莫斯)和法尼基转移酶的抑制剂(替法尼布)证明了在NHL/HD患者中的单药活性。初步的体外研究表明，Raf激酶/VGFR抑制剂索拉非尼对淋巴瘤细胞的活性与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)联合使用将提高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相互之间以及与传统化疗药物的合理组合，参与这些试验的患者的淋巴瘤细胞中的研究性生物标记物，以及将导致下一代临床试验的原发肿瘤细胞中的新药物和组合的体外研究。本研究有三个具体目的：目的1、研究PI3K/Akt/mTOR途径抑制剂与Raf-Kinase抑制剂和常规化疗药物联合应用的安全性和有效性。目的2、评价联合应用STI对靶向通路的作用，并利用AIM 1试验患者的恶性B细胞，寻找潜在的抗肿瘤效应的标志物。目的3、研究含有针对PI3K/Akt/mTOR途径的药物和其他STI或常规药物的新型组合，为下一代临床试验提供理论依据。我们的初步研究将集中在靶向PI3K/Akt/mTOR通路组件或已知与PI3K/Akt/mTOR通路相关的那些通路的药物。具有实质性临床活性的组合随后将在NCCTG或ECOG等合作小组中进行大规模测试。LASH语言陈述：淋巴瘤细胞对信号作出反应，这些信号从细胞外部传递到细胞内部，导致细胞生长。这个项目的重点是为淋巴瘤患者提供干扰这些信号的新药。对其中几种药物的初步研究是有希望的，该项目的目标将是将这些药物结合在一起并与其他常见的化疗药物结合起来，以推进淋巴瘤的治疗。