TREATMENT OF BCR/ABL CAUSED LEUKEMIAS WITH FTIs

使用 FTI 治疗 BCR/ABL 引起的白血病

• 批准号: 7265925
• 负责人: Nora C Heisterkamp
• 金额: $ 26.67万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265925
• 关键词: ATP-Binding Cassette Transporters; Acute; Acute Lymphocytic Leukemia; Antineoplastic Agents; Cell Adhesion Molecules; Cell Lineage; Cells; Characteristics; Chimeric Proteins; Chronic Myeloid Leukemia; Class; Clinical Trials; Condition; Data; Development; Disease; Drug resistance; Drug usage; Family member; Farnesyl Transferase Inhibitor; Fibroblasts; Future; Hematopoietic stem cells; Human; Imatinib; In Vitro; Leukemic Cell; Life; Long-Term Effects; Lymphoblastic Leukemia; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Minority; Modeling; Molecular Target; Mus; N-Cadherin; Numbers; Oncogenic; Patients; Pharmaceutical Preparations; Pre-B-Cell Leukemia; Research Personnel; Resistance; Resistance development; SCH 66336; Signal Transduction Inhibitor; Stromal Cells; Testing; Toxic effect; Transgenic Organisms; Tumor Burden; Tyrosine Kinase Inhibitor; base; bcr-abl Fusion Proteins; cancer cell; chemotherapy; in vivo; leukemia; leukemic stem cell; lymphoblast; malignant breast neoplasm; mouse model; novel; outcome forecast; prevent; programs; research study; small molecule

DESCRIPTION (provided by applicant): Farnesyltransferase inhibitors (FTIs) belong to a novel class of relatively non-toxic anti-cancer drugs that are currently being tested in clinical trials for a variety of cancers. Our studies have focused on exploring the utility of treating Ph-positive acute lymphoblastic leukemia (ALL) with FTIs. This type of leukemia is caused by the Bcr/Abl oncogenic fusion protein and has a very unfavorable prognosis. In the previous period of support, we showed that the FTI SCH66336 as monotherapy is extremely effective in preventing progression of pre-leukemia in a transgenic mouse model and can significantly prolong the life of mice with progressed disease and a very high tumor burden. However, drug resistance against this FTI could be readily induced both in vitro and in vivo and we identified several mechanisms that can contribute to this. Based on our preliminary data, we hypothesize, that the development of resistance of Bcr/Abl lymphoblastic leukemia cells to the FTI SCH66336 is facilitated by interactions between the microenvironment of the leukemic cells, which selects out a subpopulation of putative leukemia stem cells that is able to survive under the drug-restrictive conditions. To investigate this and to increase the efficacy of eradicating the malignant cells with FTI treatment, we propose the following Specific Aims. (1) To explore the expression and knockdown of the ABC transporter ATP11a in normal and malignant B-lineage cells and the effect of this on resistance to FTIs (2) To determine the effect of expression of the cell adhesion molecule N-cadherin in pre-B leukemia cells on their ability to resist treatment with FTIs (3) To define the characteristics of the minority subpopulations of lymphoblasts that derive protection from fibroblasts against FTI treatment and subsequently are able to grow out, including their sensitivity to other drugs with a presumed very different molecular target. Our experiments will provide important information on the mechanisms by which the Bcr/Abl expressing lymphoblasts acquire resistance to FTIs and will allow for a more optimal use of this class of drugs in the treatment of Ph-positive ALL, either as monotherapy or in combination with other drugs. FTIs belong to a novel, rapidly expanding class of promising anti-cancer drugs with relatively low toxicity. Because of this, our studies are very important in anticipating the problems that will emerge once these types of drugs are used on large numbers of human patients. Relevance: A major problem for patients who are treated with chemotherapy is that their cancer cells frequently stop responding to drug treatment. In the past 5 years there has been a spectacular development of new types of anti-cancer drugs that selectively target specific abnormal molecules in the cancer cells and that are relatively non-toxic. In anticipation of the future widespread use of such drugs to treat cancer, this project examines how cancer cells may develop resistance against these new drugs, using acute lymphoblastic leukemia and a drug (an FTI) as model.

描述（由申请人提供）：法呢基转移酶抑制剂（FTI）属于一类新型的相对无毒的抗癌药物，目前正在针对多种癌症进行临床试验。我们的研究重点是探索 FTI 治疗 Ph 阳性急性淋巴细胞白血病 (ALL) 的效用。这种类型的白血病是由Bcr/Abl致癌融合蛋白引起的，预后非常不利。在前期的支持中，我们证明FTI SCH66336作为单一疗法在转基因小鼠模型中预防白血病前期进展极为有效，并且可以显着延长疾病进展和肿瘤负荷非常高的小鼠的生命。然而，在体外和体内都可以很容易地诱导针对这种 FTI 的耐药性，我们确定了几种可能导致这种情况的机制。根据我们的初步数据，我们假设，白血病细胞微环境之间的相互作用促进了 Bcr/Abl 淋巴细胞白血病细胞对 FTI SCH66336 的耐药性的发展，从而选择了能够在药物限制条件下存活的假定白血病干细胞亚群。为了研究这一点并提高 FTI 治疗根除恶性细胞的功效，我们提出以下具体目标。 (1) 探讨 ABC 转运蛋白 ATP11a 在正常和恶性 B 系细胞中的表达和敲低，以及其对 FTI 抵抗的影响 (2) 确定前 B 白血病细胞中细胞粘附分子 N-钙粘蛋白的表达对其抵抗 FTI 治疗能力的影响 (3) 确定获得 FTI 保护的少数淋巴细胞亚群的特征 成纤维细胞抵抗 FTI 治疗，随后能够生长，包括它们对具有假定的分子靶点非常不同的其他药物的敏感性。我们的实验将提供有关表达 Bcr/Abl 的淋巴母细胞获得 FTI 耐药性的机制的重要信息，并将允许更优化地使用此类药物治疗 Ph 阳性 ALL，无论是作为单一疗法还是与其他药物联合使用。 FTI 属于一类新型、快速发展、有前景且毒性相对较低的抗癌药物。正因为如此，我们的研究对于预测一旦这些类型的药物用于大量人类患者时将会出现的问题非常重要。相关性：接受化疗的患者面临的一个主要问题是他们的癌细胞经常对药物治疗停止反应。在过去的五年里，新型抗癌药物取得了惊人的发展，这些药物选择性地针对癌细胞中的特定异常分子，并且相对无毒。预计未来此类药物将广泛用于治疗癌症，该项目以急性淋巴细胞白血病和药物（FTI）为模型，研究癌细胞如何对这些新药产生耐药性。