Assessing BIM expression as a cause and marker for resistance to targeted therapi

评估 BIM 表达作为靶向治疗耐药性的原因和标志

• 批准号: 8916050
• 负责人: Anthony Charles Faber
• 金额: $ 19.11万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916050
• 关键词: Address; Affect; Apoptosis; Apoptotic; BCL2 gene; BCL2L11 gene; Cancer Center; Cancer Model; Cancer Patient; Cell Death; Cell Line; Chromatin; Clinical; Country; DNA Sequence Alteration; Data; Disease; Down-Regulation; ERBB2 gene; Epidermal Growth Factor Receptor; Epigenetic Process; Equilibrium; Family member; General Hospitals; Generations; Genotype; Goals; Growth; Health; In Vitro; In complete remission; Laboratories; Learning; Malignant Neoplasms; Malignant neoplasm of lung; Massachusetts; Methods; Modeling; Mutation; Oncogenes; Outcome; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Population; Progressive Disease; Regimen; Relative (related person); Resistance; Resistance development; Signal Transduction; Technology; Testing; Therapeutic; Translational Research; Treatment outcome; alternative treatment; base; cancer cell; falls; genetic analysis; improved; in vivo; malignant breast neoplasm; mimetics; mutant; oncogene addiction; patient population; pro-apoptotic protein; research study; resistance mechanism; response; targeted cancer therapy; targeted treatment; therapy resistant; treatment strategy

DESCRIPTION (provided by applicant): Over, the past several years, we have learned that subsets of genetically defined cancers require an activated kinase for their growth and survival. In these cancers, the kinase is often directly activated by genetic alteration; mutation, amplification or translocation. These cancer cells are "addicted" to the genetically activated kinase, and they die, via apoptosis, upon inhibition of the kinase. This is known as "targeted therapy." These findings have already had a transformative impact on cancer therapeutics. In 2009, Massachusetts General Hospital (MGH) created a Translational Research Laboratory to perform multiplexed genetic analyses on the lung cancers of all patients being treated at MGH, and we have genotyped over 600 cases in the past year. This technology is quickly being implemented at many other cancer centers throughout the country, highlighting the importance of this burgeoning field. Intriguingly, while many of these genetically defined cancers (such as EGFR mutant and ALK translocated) have dramatic responses following targeted therapies, some have either poor responses or no responses, for largely unknown reasons. While resistance in some of these cancers are thought to be caused by secondary mutations that result in sustained intracellular signaling in the presence of targeted therapy, a large population of patients, whom do not carry these mutations in their cancers, are resistant for unknown reasons. We have found that targeted therapies are most effective when they induce both growth arrest and cell death (apoptosis). When they fail to, responses are mitigated. The inadequacy of targeted therapies to induce apoptosis may be caused by a deficiency in the pro-apoptotic protein, BIM. In this application, we propose that, in the setting of oncogene addiction, resistance arises when targeted therapies fail to induce apoptosis in oncogene-addicted cancers, despite downregulation of the intracellular signaling and posit that these cancers fail to undergo apoptosis because of deficiencies in the expression of BIM. We highlight preliminary data that supports these hypotheses, including functional in vitro and in vivo analyses, predictive power of BIM expression to apoptosis in cell line models, and patient data suggesting BIM expression can prospectively predict patient response to EGFR mutant targeted therapies. Lastly, we discuss potential, testable pharmaceutical strategies to overcome BIM deficiency in these cancers. If our testable hypothesis is proven correct, determining BIM expression in pre-treatment levels of oncogene- addicted cancers will change the way this growing population of cancer patients is treated.

描述（由申请人提供）：在过去的几年中，我们已经了解到，基因定义的癌症的子集需要活化的激酶来促进其生长和存活。在这些癌症中，激酶通常通过遗传改变、突变、扩增或易位直接激活。这些癌细胞对遗传活化的激酶“上瘾”，并且在激酶被抑制后，它们通过细胞凋亡而死亡。这就是所谓的“靶向治疗。“这些发现已经对癌症治疗产生了变革性的影响。2009年，马萨诸塞州总医院（MGH）创建了一个转化研究实验室，对在MGH接受治疗的所有肺癌患者进行多重基因分析，我们在过去一年中对600多例病例进行了基因分型。这项技术正在全国许多其他癌症中心迅速实施，凸显了这一新兴领域的重要性。有趣的是，虽然许多这些基因定义的癌症（如EGFR突变体和ALK易位）在靶向治疗后有显著的反应，但有些癌症的反应很差或没有反应，原因很大程度上未知。虽然这些癌症中的一些的抗性被认为是由在靶向治疗存在下导致持续的细胞内信号传导的继发性突变引起的，但是大的群体中的许多人都认为， 的患者，他们的癌症中没有携带这些突变，但由于未知的原因而产生耐药性。我们已经发现，靶向治疗是最有效的，当他们诱导生长停滞和细胞死亡（凋亡）。如果他们不这样做，反应就会减轻。诱导细胞凋亡的靶向治疗的不足可能是由促凋亡蛋白BIM的缺乏引起的。在本申请中，我们提出，在癌基因成瘾的情况下， 当靶向治疗不能诱导癌基因成瘾性癌症的细胞凋亡时，尽管细胞内信号转导下调， 由于BIM表达的缺陷而发生凋亡。我们强调支持这些假设的初步数据，包括体外和体内功能分析，预测 BIM表达对细胞系模型中细胞凋亡的影响，以及提示BIM表达可前瞻性预测患者对EGFR突变体靶向治疗的反应的患者数据。最后，我们讨论了潜在的，可测试的药物策略，以克服这些癌症中的BIM缺陷。如果我们的可测试假设被证明是正确的，那么确定癌基因成瘾癌症治疗前水平的BIM表达将改变不断增长的癌症患者群体的治疗方式。