Signal transduction inhibitor therapy for Lymphoma

淋巴瘤的信号转导抑制剂治疗

• 批准号: 7249113
• 负责人: Thomas E. Witzig
• 金额: $ 32.88万
• 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/7249113
• 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 Chemotherapy; 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; R115777 (Zarnestra); Radioimmunoconjugate; Raf Kinase Inhibitor; Rate; 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; bleomycin/dacarbazine/doxorubicin/vinblastine protocol; cell growth; chemotherapy; improved; inhibitor/antagonist; 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）：过去几十年来，非霍奇金淋巴瘤（NHL）和霍奇金病（HD）的治疗进展提高了患有这些常见恶性肿瘤的患者的生存率。然而，近 40% 的大细胞 NHL 患者、80% 的惰性 NHL 患者和 20% 的 HD 患者未治愈并死于疾病。很明显，需要基于淋巴瘤细胞信号转导途径知识的具有独特作用机制的新药物来推进淋巴瘤治疗。该提案重点关注淋巴瘤细胞中的磷脂酰肌醇 3 激酶 (PI3K) 和 Raf 激酶途径。我们已经证明使用 PI3K 通路抑制剂（替西罗莫司/依维莫司）和法呢基转移酶抑制剂（替比法尼）对 NHL/HD 患者具有单药活性。初步体外研究表明，Raf 激酶/VGFR 抑制剂索拉非尼对抗淋巴瘤细胞的活性与 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。为了检验这一假设，该项目包括评估性传播感染相互之间以及与传统化疗药物的合理组合的临床试验，参与这些试验的患者的淋巴瘤细胞中的研究生物标志物，以及原发性肿瘤细胞中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 激酶抑制剂和常规化疗药物联合使用的安全性和有效性。目标 2，评估 STI 组合对靶向途径的作用，并使用参与目标 1 试验的患者的恶性 B 细胞确定抗肿瘤功效的潜在标志物。目标 3，研究含有靶向药物的新型组合体外恶性 B 细胞中的 PI3K/Akt/mTOR 通路和其他 STI 或常规药物，为下一代临床试验提供理论依据。我们的初步研究将集中于针对 PI3K/Akt/mTOR 通路成分或已知与 PI3K/Akt/mTOR 通路相关的通路成分的药物。具有实质性临床活动的组合随后将在 NCCTG 或 ECOG 等合作小组中进行大规模测试。外行语言陈述：淋巴瘤细胞对从细胞外部传输到内部的信号做出反应，导致细胞生长。该项目的重点是为淋巴瘤患者开发干扰这些信号的新药。对其中几种药物的初步研究很有希望，该项目的目标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。