Mechanisms of Tyrosine Kinase Inhibitor Resistance in GI Stromal Tumors

胃肠道间质瘤酪氨酸激酶抑制剂耐药机制

• 批准号: 8258641
• 负责人: Michael C Heinrich
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258641
• 关键词: Accounting; Acute Myelocytic Leukemia; Adult; Adverse effects; Adverse reactions; Age; Alleles; American; Apoptosis; BAY 54-9085; Biochemical; Biological Assay; Biological Models; Budgets; Cancer Biology; Caring; Cell Line; Cell model; Cells; Chinese Hamster Ovary Cell; Clinical; Clinical Trials; Cloning; Colon Carcinoma; Combined Modality Therapy; Comorbidity; Cytoplasmic Tail; Cytotoxic agent; DNA; Dasatinib; Development; Diabetes Mellitus; Diagnosis; Drug resistance; Effectiveness; Ethylnitrosourea; Frequencies; Gastrointestinal Stromal Tumors; Genomics; Genotype; Health; Healthcare; High Pressure Liquid Chromatography; Hospitalization; Imatinib; In Vitro; Investigation; Laboratories; Life; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measurement; Modeling; Morbidity - disease rate; Mucositis; Mutagenesis; Mutation; Neutropenic Fever; Oncogenic; PDGFRA gene; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Pulmonary Heart Disease; Quality of life; Radiation; Receptor Protein-Tyrosine Kinases; Recurrence; Research; Resistance; Risk; Role; Seminoma; Signal Transduction; Signaling Molecule; Solid Neoplasm; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stromal Neoplasm; System; Techniques; Testing; Therapeutic Agents; Time; Toxic effect; Transfection; Treatment outcome; Tumor Biology; Tyrosine Kinase Inhibitor; Unresectable; Variant; Veterans; advanced disease; base; cancer care; cancer therapy; chemotherapy; clinically relevant; conventional therapy; cost; extracellular; improved; inhibitor/antagonist; insight; kinase inhibitor; malignant breast neoplasm; mastocytosis; medical complication; melanoma; mortality; mutant; novel; novel therapeutics; prevent; programs; research study; resistance mechanism; sarcoma; small molecule; soft tissue; treatment strategy; tumor; tumor progression

DESCRIPTION (provided by applicant): Gastrointestinal stromal tumors (GISTs), the most common type of adult soft tissue sarcoma, are diagnosed in approximately 5,000-10,000 Americans each year. Genomic activation of KIT or PDGFRA receptor tyrosine kinases plays a role in the development of ~85% of GISTs. Imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), has revolutionized the treatment of patients with advanced, unresectable GIST. Nevertheless, primary resistance to the drug is observed in some patients and secondary (acquired) resistance occurs with increasing frequency over time. The median time to tumor progression during front-line imatinib therapy is only 18-22 months. Notably, in the majority of treated GISTs, imatinib resistance results from selection of clones with drug-resistant kinase mutations. Hypothesis: the most efficient pathway for optimizing the treatment of patients with advanced GIST is to identify the relevant mechanisms of TKI-resistance and establish model systems that allow the testing of alternative or complementary agents, including combination therapy. Specific Aim 1. Using cell-based models, we will identify and validate treatment strategies to circumvent and/or prevent the emergence of secondary resistance to TKIs caused by the selection of tumor subclones with acquired KIT kinase mutations. This aim will utilize two different cellular models: 1) a transient transfection expression system to biochemically profile the activity of our panel of TKIs against previously identified imatinb-resistant mutant kinases; and 2) an ENU-mutagenesis/TKI drug selection system to identify novel KIT kinase mutations that confer TKI-resistance. Specific Aim 2. To determine the frequency and spectrum of secondary KIT (or PDGFRA) kinase mutations present in TKI-resistant clinical specimens. Clinical specimens will be obtained from patients treated with two or more successive TKIs (e.g imatinib followed by sunitinib). Novel kinase mutations that are identified will be cloned and biochemically characterized as described above. Potential impact on Veterans Health Care: Cancer is a major cause of morbidity and mortality in American veterans, especially in veterans over the age of 50. The development of new cancer therapeutic agents that target pathogenetic or significant aspects of tumor biology would greatly increase the quality and duration of life for veterans with cancer. PUBLIC HEALTH RELEVANCE: Relevance to Veterans Health Cancer is a major cause of morbidity and mortality in American veterans, especially in veterans over the age of 50. The care of veterans with cancer represents a significant portion of the overall Veterans Affairs Health Care budget. The development of new cancer therapeutic agents that target pathogenetic or significant aspects of tumor biology will greatly increase the quality of life of veterans with cancer. Such targeted agents have the potential to be much more effective than conventional treatments and with significantly less toxicity. Reducing toxicity of cancer treatments should reduce cancer care costs by decreasing hospitalizations for side effects of cancer treatment (such as neutropenic fever and/or mucositis). Decreasing treatment-related medical complications is of particular relevance to the treatment of veterans who often have significant co-morbidities such as cardiopulmonary disease and/or diabetes that increase the risk of adverse reactions to conventional cytotoxic agents. The model to be studied in the current application has direct relevance to patients with Gastrointestinal Stromal Tumors, but will likely provide major insights into cancer biology and the mechanisms of resistance to other small molecule kinase inhibitors. These insights will be directly applicable to improving the treatment of other malignancies that are dependent upon KIT and/or PDGFRA signaling (e.g. melanoma, acute myeloid leukemia, seminoma, and mastocytosis). However, the results for this project will also be valuable for the evolving development of molecularly targeted therapies for the more common solid tumors such as lung, colon, prostate, and breast cancer.

描述（由申请人提供）： 胃肠道肿瘤（GIST）是最常见的成年软组织肉瘤类型，每年大约有5,000-10,000名美国人被诊断出。试剂盒或PDGFRA受体酪氨酸激酶的基因组激活在约85％的GIST的发展中起作用。伊马替尼（Imatinib）是一种试剂盒/PDGFRA酪氨酸激酶抑制剂（TKI），已彻底改变了治疗晚期，无法切除的要点的患者。然而，在某些患者中观察到对药物的一级耐药性，并且随着时间的推移频率增加，次级（获得的）耐药性发生。前线伊马替尼治疗期间肿瘤进展的中位时间仅为18-22个月。值得注意的是，在大多数经过治疗的GIST中，伊马替尼的耐药性是由于选择具有抗药性激酶突变的克隆而导致的。假设：优化高级GIST患者治疗的最有效途径是确定TKI抗性的相关机制，并建立模型系统，允许测试替代或互补药物（包括组合疗法）。特定目标1。使用基于细胞的模型，我们将识别和验证治疗策略，以绕过和/或防止因选择获得的KIT激酶突变的肿瘤亚克隆引起的二级抗TKIS的出现。该目标将利用两个不同的细胞模型：1）瞬时转染表达系统在生物化学上介绍了我们TKI面板对先前鉴定的IMATINB耐药突变激酶的活性； 2）ENU-rutagenesis/TKI药物选择系统，以识别赋予TKI抗性的新型试剂酶激酶突变。具体目标2。确定耐TKI临床样本中存在的次级试剂盒（或PDGFRA）激酶突变的频率和光谱。将从连续两次或多个TKIS治疗的患者（例如伊马替尼，然后是舒尼替尼）获得临床标本。如上所述，鉴定出的新型激酶突变将被克隆和生化表征。对退伍军人卫生保健的潜在影响：癌症是美国退伍军人发病和死亡率的主要原因，尤其是在50岁以上的退伍军人中。针对肿瘤生物学的致病或重要方面的新型癌症治疗剂的发展将大大提高癌症退伍军人的寿命和寿命。 公共卫生相关性： 与退伍军人卫生癌症的相关性是美国退伍军人发病率和死亡率的主要原因，尤其是在50岁以上的退伍军人中。对癌症的退伍军人的护理是整体退伍军人事务医疗保健预算的很大一部分。针对肿瘤生物学的致病或重要方面的新癌症治疗剂的发展将大大提高退伍军人的癌症生活质量。这种靶向药物具有比常规治疗更有效的潜力，并且毒性明显更少。降低癌症治疗的毒性应通过减少癌症治疗副作用（例如中性粒细胞热和/或粘膜炎）的住院来降低癌症护理成本。减少与治疗相关的医疗并发症特别与经常患有明显的合并症的退伍军人（例如心肺疾病和/或糖尿病）的治疗特别相关，这些治疗增加了对常规细胞毒性剂的不良反应风险。当前应用中要研究的模型与胃肠道肿瘤患者具有直接相关性，但可能会提供对癌症生物学的主要见解以及对其他小分子激酶抑制剂的耐药机制。这些见解将直接适用于改善依赖盒子和/或PDGFRA信号传导的其他恶性肿瘤（例如黑色素瘤，急性髓样白血病，精神分裂瘤和肥大性细胞增多症）。但是，该项目的结果对于对肺，结肠癌，前列腺和乳腺癌等更常见的实体瘤的分子靶向疗法的发展也很有价值。