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亚群需要激活的激酶来促进其生长和存活。在这些癌症中，激酶通常通过基因改变直接激活；突变、扩增或易位。这些癌细胞对基因激活的激酶“上瘾”，当激酶受到抑制时，它们会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接受治疗的所有患者的肺癌进行多重基因分析，在过去的一年里，我们已经对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，突出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突变和ALK易位）在靶向治疗后有显着的反应，但由于很大程度上未知的原因，一些反应很差或没有反应。虽然这些癌症中的一些耐药被认为是由继发性突变引起的，这些突变在靶向治疗的存在下导致持续的细胞内信号传导，但大量人群