TOR kinase inhibitors for leukemia therapy: mechanisms of action and resistance

用于白血病治疗的 TOR 激酶抑制剂：作用机制和耐药性

基本信息

批准号：
8628792
负责人：
DAVID Alexander FRUMAN
金额：
$ 30.18万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-12 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628792
关键词：
1-Phosphatidylinositol 4-Kinase Active Sites Address Animals Antibodies Apoptosis Apoptotic B lymphoid malignancy B-Lymphocytes BCL2 gene Biological Assay Biological Markers CCI-779 Cancer Patient Cause of Death Cell Death Cell Line Cells Chronic Lymphocytic Leukemia Clinical Clinical Trials Complex Data Development Drug Combinations Drug resistance Enzymes Equilibrium Exhibits Family member Gene Targeting Genetic Goals Growth Health Human Imatinib Immune Immunosuppressive Agents In Vitro Journals Knock-out Laboratories Learning Link Lipids Malignant Neoplasms Mediating Modeling Molecular Molecular Mechanisms of Action Molecular Target Multiprotein Complexes Mus Nature Oncogenes Output Paper Pathway interactions Pharmaceutical Preparations Phase I Clinical Trials Phosphatidylinositols Phosphotransferases Physiological Processes Protein Kinase Proto-Oncogene Proteins c-akt Relative (related person)Resistance Role Signal Pathway Signal Transduction Sirolimus Solid Neoplasm System T-Lymphocyte Testing Therapeutic Toxic effect Tumor Cell Line Tyrosine Kinase Inhibitor Work Xenograft Model bcr-abl Fusion Proteins cancer cell cancer therapy cellular targeting drug development drug discovery drug sensitivity human FRAP1 protein improved in vivo inhibitor/antagonist killings kinase inhibitor leukemia leukemia/lymphoma neoplastic cell novel pre-clinical resistance mechanism response rituximab small hairpin RNA small molecule success tool transcription factor weapons

项目摘要

DESCRIPTION (provided by applicant): Most cancer cells display activation of phosphoinositide 3-kinase (PI3K) and the downstream enzymes AKT and TOR. Targeting the PI3K/AKT/TOR network is a promising strategy for cancer therapeutics, yet it is not clear which target profile will provide the best balance of efficacy and tolerability. Compounds that partially inhibit TOR (such as rapamycin) or compounds that inhibit both PI3K and TOR (such as PI-103) have significant limitations in efficacy and/or tolerability. A major breakthrough in this field has been the identification of novel compounds that are highly potent, selective, small molecule competitive inhibitors of TOR. Termed "active-site TOR inhibitors", these compounds fully inhibit the TOR enzyme when it is present in TORC1 or TORC2, two distinct multiprotein complexes. Compared to rapamycin, an allosteric inhibitor, active-site TOR inhibitors have a broader effect on key signaling pathways and are more effective at suppressing survival of murine and human leukemia cells. Remarkably, these compounds are less immunosuppressive than rapamycin despite their greater anti-leukemic efficacy. Active-site TOR inhibitors appear equally effective in leukemia models as the less selective PI3K/TOR inhibitors, yet are considerably better tolerated in mice. Several active-site TOR inhibitors are in early stage clinical trials. The overall objective of this proposal is to refine and extend our understanding of active-site TOR inhibitors, with the ultimate goal of improving the health of cancer patients. We will focus on B cell malignancies, since active-site TOR inhibitors have dramatic effects in B cell leukemia models yet the mechanism of action remains poorly understood. The proposal has two specific aims. First, we will establish the mechanisms by which active-site TOR inhibitors trigger leukemia cell death. In this aim we will use genetic approaches to test the hypothesis that both TORC1 and TORC2 mediate survival signaling in leukemia cells. This will be accomplished using inducible Cre-mediated knockout systems and shRNA-mediated knockdown. We will then test the roles of TORC1 and TORC2 substrates in maintaining survival in leukemia cells. Second, we will define mechanisms of cellular resistance to active-site TOR inhibitors. As with any targeted molecular approach, subtypes of cancer cells display differing sensitivity to active-site TOR inhibitors. An emerging theme in drug development is the need to identify effective combinations of targeted agents. Using cell lines that do not undergo apoptosis in response to TOR inhibition, we will use candidate and global approaches to identify druggable mechanisms of resistance. We will then test combination strategies in vitro and in vivo. Identifying mechanisms of resistance and applying appropriate drug combinations will broaden the potential application of active-site TOR inhibitors.

描述（由申请人提供）：大多数癌细胞表现出磷酸肌醇 3-激酶 (PI3K) 及其下游酶 AKT 和 TOR 的激活。靶向 PI3K/AKT/TOR 网络是一种有前途的癌症治疗策略，但尚不清楚哪种靶点能够提供疗效和耐受性的最佳平衡。部分抑制 TOR 的化合物（例如雷帕霉素）或同时抑制 PI3K 和 TOR 的化合物（例如 PI-103）在功效和/或耐受性方面具有显着的局限性。该领域的一项重大突破是鉴定出新型化合物，它们是高效、选择性、小分子竞争性 TOR 抑制剂。这些化合物被称为“活性位点 TOR 抑制剂”，当 TOR 酶存在于两种不同的多蛋白复合物 TORC1 或 TORC2 中时，可完全抑制 TOR 酶。与变构抑制剂雷帕霉素相比，活性位点 TOR 抑制剂对关键信号通路具有更广泛的影响，并且在抑制小鼠和人类白血病细胞的存活方面更有效。值得注意的是，尽管这些化合物具有更强的抗白血病功效，但其免疫抑制作用却低于雷帕霉素。活性位点 TOR 抑制剂在白血病模型中与选择性较低的 PI3K/TOR 抑制剂同样有效，但在小鼠中的耐受性要好得多。几种活性位点 TOR 抑制剂正处于早期临床试验阶段。该提案的总体目标是完善和扩展我们对活性位点 TOR 抑制剂的理解，最终目标是改善癌症患者的健康。我们将重点关注 B 细胞恶性肿瘤，因为活性位点 TOR 抑制剂在 B 细胞白血病模型中具有显着效果，但其作用机制仍知之甚少。该提案有两个具体目标。首先，我们将建立活性位点 TOR 抑制剂触发白血病细胞死亡的机制。为此，我们将使用遗传学方法来检验 TORC1 和 TORC2 介导白血病细胞生存信号传导的假设。这将通过使用诱导型 Cre 介导的敲除系统和 shRNA 介导的敲低来完成。然后我们将测试 TORC1 和 TORC2 底物在维持白血病细胞存活中的作用。其次，我们将定义细胞对活性位点 TOR 抑制剂的耐药机制。与任何靶向分子方法一样，癌细胞亚型对活性位点 TOR 抑制剂表现出不同的敏感性。药物开发中的一个新兴主题是需要确定靶向药物的有效组合。使用不会因 TOR 抑制而发生凋亡的细胞系，我们将使用候选方法和全局方法来识别可药物化的耐药机制。然后我们将在体外和体内测试组合策略。识别耐药机制并应用适当的药物组合将拓宽活性位点 TOR 抑制剂的潜在应用。