Signal Transduction Inhibitor Therapy for Lymphoma

淋巴瘤的信号转导抑制剂治疗

• 批准号: 7254591
• 负责人: Thomas E. Witzig
• 金额: $ 32.03万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254591
• 关键词: 1-Phosphatidylinositol 3-Kinase; Apoptosis; B lymphoid malignancy; B-Lymphocytes; BAY 54-9085; Bioinformatics; Biological Markers; Biostatistics Core; Cell Line; Cell Proliferation; Cell physiology; Cells; Clinical; Clinical Research; Clinical Trials; Combination Chemotherapy; Common Neoplasm; Conduct Clinical Trials; Development; Disease; Drug Delivery Systems; Eastern Cooperative Oncology Group; Farnesyl Transferase Inhibitor; Funding; Future; Goals; Hodgkin Disease; In Vitro; Indolent; Investigation; Iowa; Knowledge; Language; Lead; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mantle Cell Lymphoma; Multiple Myeloma; New Agents; Non-Hodgkin' s Lymphoma; North Central Cancer Treatment Group; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phosphotransferases; Primary Neoplasm; Proteins; Proto-Oncogene Proteins c-akt; R115777 (Zarnestra); Radioimmunoconjugate; Raf Kinase Inhibitor; Rate; Receptor Protein-Tyrosine Kinases; Regulation; Relapse; Reproduction spores; 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; bleomycin/dacarbazine/doxorubicin/vinblastine protocol; career; cell growth; chemotherapy; improved; inhibitor/antagonist; member; neoplastic cell; next generation; novel; programs; raf Kinases; research and development; response; rituximab; tumor

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.

在最后几个 数十年来改善了这些常见恶性肿瘤患者的生存。但是，将近40％ 大细胞NHL的患者，80％的懒惰NHL和20％的HD患者无法治愈并死于其疾病。 显然，具有基于信号转导知识的独特作用机理的新代理 需要淋巴瘤细胞中的途径来改进淋巴瘤治疗。该提议重点是 淋巴瘤细胞中的磷脂酰肌醇-3激酶（PI3K）和RAF激酶途径。我们已经证明了 使用PI3K途径抑制剂（Temsirolimus/everolimus）的NHL/HD患者的单药活性 和Farnesyl转移酶（Tipifarnib）的抑制剂。初步的体外研究证明了RAF的活性 激酶/VGFR抑制剂索拉非尼针对与PI3K途径抑制剂协同作用的淋巴瘤细胞。 该提议的总体假设是化学疗法与一个或多个的结合 信号转导抑制剂（STI）将提高NHL/HD患者的反应率和存活率。到 检验该假设，该项目包括评估性传播感染合理组合的临床试验 其他且与常规化学疗法剂一起研究患者的淋巴瘤细胞中的生物标志物 参加这些试验，并在原发性肿瘤细胞中对新药物的体外研究和组合 导致下一代临床试验。这项工作以3个特定目标组织。 目的1，研究PI3K/AKT/MTOR途径抑制剂的安全性和功效 激酶抑制剂和常规化疗剂 目标2，以评估性传播感染对靶向途径的组合的作用并确定的潜在标记 使用来自AIM 1的试验中的患者的恶性B细胞使用恶性B细胞的抗肿瘤功效 AIM 3，研究含有靶向PI3K/AKT/MTOR途径和其他靶向剂的新型组合 在体外恶性B细胞中的性传播剂或常规代理，为下一代提供理由 临床试验。我们的最初研究将集中于针对PI3K/AKT/MTOR途径成分的药物或 已知与PI3K/AKT/MTOR途径连接的途径。与大量临床的组合 然后，在NCCTG或ECOG等合作组中，活动将转变为大规模测试。 外行语言陈述：淋巴瘤细胞对从外部传播到的信号做出反应 细胞内部导致细胞生长。该项目着重于针对淋巴瘤患者的新药 干扰这些信号。其中几种药物的初步研究很有希望，这是目标 项目将是将这些药物和其他常见的化学疗法剂相结合，以推动 淋巴瘤的治疗。