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存活。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，并且死于其疾病。显然，基于对淋巴瘤细胞中信号转导途径知识的知识，具有独特作用机理的新药物是为了推进淋巴瘤治疗。该提议着重于淋巴瘤细胞中的磷脂酰肌醇-3激酶（PI3K）和RAF激酶途径。我们已经使用PI3K途径（Temsirolimus/everolimus）和Farnesyl转移酶（Tipifarnib）的抑制剂（Tipifarnib）证明了NHL/HD患者的单一药物活性。初步的体外研究表明，RAF激酶/VGFR抑制剂索拉非尼对与PI3K途径抑制剂协同作用的淋巴瘤细胞的活性。该提案的总体假设是，化学疗法与一种或多种信号转导抑制剂（STI）的结合将提高NHL/HD患者的反应率和存活率。为了检验这一假设，该项目包括评估性传播性传播感染的临床试验，这些试验彼此之间以及常规化疗剂的合理组合，研究了参加这些试验的患者的淋巴瘤细胞中的生物标志物，以及对新药物的体外研究以及将导致下一代临床试验的原发性肿瘤细胞的结合。这项工作是在3个特定目标中组织的：目标1，以研究PI3K/AKT/MTOR途径抑制剂与RAF-激酶抑制剂和常规化学疗法剂的安全性和功效。目的2，以评估性传播性传播感染对靶向途径的组合的作用，并使用来自AIM 1的试验中的患者的恶性B细胞来确定抗肿瘤功效的潜在标志。AIM 3。目标3，研究含有针对PI3K/AKT/MTOR途径的PII3K/AKT/MTOR途径和其他clainity of Clinational of Clination clantial of Clinational of Sertanitial B-Cells ventros ventry B-Cells的新型组合，该组合是在AIM 1中使用的。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途径相连的途径。然后，与大量临床活性的组合将转化为NCCTG或ECOG等合作组中的大规模测试。外行语言陈述：淋巴瘤细胞对从外部传播到细胞内部传播的信号导致细胞生长的响应。该项目着重于干扰这些信号的淋巴瘤患者的新药。使用其中几种药物的初步研究很有希望，该项目的目的是将这些药物和其他常见的化学疗法剂结合在一起，以促进淋巴瘤的治疗。