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.

过去几年非霍奇金淋巴瘤 (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生存率得到了改善。然而，近 40% 大细胞 NHL 患者、80% 惰性 NHL 患者和 20% HD 患者未治愈并死于疾病。 很明显，基于信号转导知识的具有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。该提案的重点是 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/依维莫司）治疗 NHL/HD 患者的单药活性 和法呢基转移酶抑制剂（替比法尼）。初步体外研究证明 Raf 的活性 激酶/VGFR 抑制剂索拉非尼针对淋巴瘤细胞，与 PI3K 通路抑制剂具有协同作用。 该提案的总体假设是化疗药物与一种或多种药物的组合 信号转导抑制剂（STI）将提高 NHL/HD 患者的缓解率和生存率。到 检验这一假设，该项目包括评估性传播感染与每种疾病的合理组合的临床试验 其他和常规化疗药物、患者淋巴瘤细胞中的研究生物标志物 参与这些试验，以及在原发性肿瘤细胞中进行新药物和组合的体外研究，这将 导致下一代临床试验。这项工作有 3 个具体目标。 目标 1，研究 PI3K/Akt/mTOR 通路抑制剂与 Raf- 联合使用的安全性和有效性 激酶抑制剂和常规化疗药物 目标 2，评估 STI 组合对目标途径的作用并确定潜在的标志物 使用参加目标 1 试验的患者的恶性 B 细胞的抗肿瘤功效 目标 3，研究包含靶向 PI3K/Akt/mTOR 通路和其他药物的新型组合 STI 或传统药物在体外作用于恶性 B 细胞，为下一代治疗提供理论依据 临床试验。我们的初步研究将集中于针对 PI3K/Akt/mTOR 通路成分的药物或那些 已知与 PI3K/Akt/mTOR 通路连接的通路。与大量临床的组合 然后，活动将转向在 NCCTG 或 ECOG 等合作组织中进行大规模测试。 外行语言陈述：淋巴瘤细胞对从外部传输到外部的信号做出反应 细胞内部导致细胞生长。该项目专注于治疗淋巴瘤患者的新药 干扰这些信号。对其中几种药物的初步研究是有希望的，其目标是 该项目将把这些药物结合起来，并与其他常见的化疗药物结合起来，以推进 淋巴瘤的治疗。