Identification of Resistance Mechanisms to Anaplastic Lymphoma Kinase Inhibitors

间变性淋巴瘤激酶抑制剂耐药机制的鉴定

• 批准号: 8598806
• 负责人: Jeffrey A. Engelman
• 金额: $ 34.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-20 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598806
• 关键词: Adenocarcinoma; Affect; Applications Grants; Biological Markers; Biological Models; Biopsy; Bypass; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Cycle Arrest; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Chromosomal Rearrangement; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Coupled; DNA Sequence Rearrangement; Data; Defect; Development; Disease; Disease remission; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Future; Gatekeeping; Gefitinib; Gene Expression Profiling; Genotype; Goals; Growth; In Vitro; Institution; Institutional Review Boards; Laboratories; Laboratory Study; Life; Malignant Neoplasms; Malignant Pleural Effusion; Malignant neoplasm of lung; Mediating; Methodology; Methods; Modeling; Molecular; Molecular Target; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Operative Surgical Procedures; Pathway interactions; Patients; Phase I Clinical Trials; Protein Tyrosine Kinase; Protocols documentation; Relapse; Research Infrastructure; Resistance; Resistance development; Sampling; Seminal; Signal Pathway; Specimen; Testing; Therapeutic; Translating; Tyrosine Kinase Inhibitor; United States; Xenograft Model; anaplastic lymphoma kinase; base; cell growth; chemotherapy; clinical infrastructure; clinical remission; clinically relevant; combinatorial; comparative genomic hybridization; design; genome-wide; improved; in vivo; kinase inhibitor; mutant; never smoker; novel; novel therapeutic intervention; repository; resistance mechanism; resistance mutation; response; subcutaneous; tumor; tumor xenograft

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States. Over the last decade, a number of new therapies targeting signaling pathways that control cell growth and survival have been developed. Some of these, particularly tyrosine kinase inhibitors (TKIs), have shown remarkable antitumor activity in select subsets of lung cancer patients. Examples include gefitinib or erlotinib for EGFR- mutant lung cancers and more recently, crizotinib (PF-02341066) for lung cancers harboring chromosomal rearrangements of ALK (anaplastic lymphoma kinase). These therapies often induce marked responses and clinical remissions; however, cancers invariably develop resistance to TKI therapy, usually within one year of treatment. This type of resistance is termed acquired resistance, and it has severely curbed the impact of these new therapies. In this application, we will focus on ALK-positive lung cancers which affect approximately 8,000 people per year in the United States alone. We have previously shown that the lung cancer patients most likely to harbor ALK rearrangements are the young, never smokers with the adenocarcinoma type of NSCLC. In a seminal phase 1 trial led by our institution, crizotinib induced significant responses in close to 60% of ALK-positive patients, and stabilized disease in an additional 30%. Most patients, however, relapse after approximately one year due to acquired resistance, and there are currently no second-line options for these resistant patients other than standard chemotherapy. Here, we propose methods to discover molecular mechanisms underlying acquired resistance to crizotinib. We will generate laboratory models of ALK-positive NSCLC from patients with the disease. Models that are not already resistant will be made resistant in the laboratory using methodology that we previously used to identify clinically validated mechanisms of EGFR TKI resistance. We will systematically assess each model for the presence of resistance mutations within ALK itself, for activation of alternative growth pathways that allow cells to bypass ALK, and for defects in the cell death machinery. We will also take more unbiased approaches like gene expression profiling and comparative genomic hybridization to discover potentially novel mechanisms of resistance. Based on our findings, we will design and test therapeutic strategies to overcome resistance in vivo. We will also confirm that these resistance mechanisms are clinically relevant by evaluating resistant tumor specimens from patients. Taken together, these studies will enable the rational selection of subsequent, or second-line, treatments for patients who relapse on crizotinib based on the identified mechanism of resistance. These basic studies will therefore translate into new therapeutic approaches in the clinic that provide long lasting and meaningful benefit to our patients.

描述（由申请人提供）：非小细胞肺癌（NSCLC）是美国癌症死亡的主要原因。在过去的十年中，已经开发了许多针对控制细胞生长和存活的信号通路的新疗法。其中一些，尤其是酪氨酸激酶抑制剂（TKI），在肺癌患者的精选亚群中表现出显着的抗肿瘤活性。例子包括用于EGFR突变肺癌的吉非替尼或Erlotinib，以及最近的Crizotinib（PF-02341066），用于肺癌的肺癌（伴有烷基染色体重排）（播种型淋巴瘤淋巴瘤激酶）。这些疗法通常会引起明显的反应和临床缓解。但是，通常在治疗后一年内，癌症总是会产生对TKI治疗的抵抗力。这种类型的电阻称为获得的抗性，并且严重遏制了这些新疗法的影响。在此应用程序中，我们将专注于仅在美国每年影响约8,000人的ALK阳性肺癌。我们以前已经表明，最有可能怀有ALK重排的肺癌患者是年轻的，从来没有吸烟者患有腺癌类型的NSCLC。在我们机构领导的一项开创性的1阶段试验中，crizotinib在近60％的ALK阳性患者中引起了显着的反应，并在另外30％的情况下稳定了疾病。然而，由于获得了抗药性，大多数患者在大约一年后复发，并且除标准化学疗法以外，目前尚无其他二线选择。在这里，我们提出了发现对克唑替尼获得抗性的分子机制的方法。我们将从患有该疾病的患者中生成ALK阳性NSCLC的实验室模型。尚未抗性的模型将在实验室中使用我们以前用来鉴定临床验证的EGFR TKI耐药机制的方法制造抗性。我们将系统地评估每个模型的ALK本身中存在电阻突变，以激活允许细胞绕过ALK的替代生长途径以及细胞死亡机械中的缺陷。我们还将采用更公正的方法，例如基因表达分析和比较基因组杂交，以发现潜在的新型抗性机制。根据我们的发现，我们将设计和测试治疗策略，以克服体内抗性。我们还将通过评估患者的耐药性肿瘤标本在临床上与临床相关。综上所述，这些研究将使随后的或二线的合理选择基于确定的抗药性机制，对在克唑替尼复发的患者进行了合理选择。因此，这些基础研究将转化为诊所中新的治疗方法，为我们的患者提供持久和有意义的好处。