c-Myc modulation and its implications in EGFR-targeted cancer therapy

c-Myc 调节及其对 EGFR 靶向癌症治疗的影响

基本信息

批准号：
10427217
负责人：
Shi-Yong Sun
金额：
$ 17.64万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427217
关键词：
Address Animal Model Apoptotic Area Biochemical Biological Biological Assay Cancer Patient Cancer cell line Cell Line Cell Proliferation Cell Survival Chromosomal translocation Clinic Clinical Clinical Treatment Data Development Disease Progression Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Event Exons FDA approved Family member Future Gefitinib Gene Amplification Generations Genes Glutamine Goals Human Human Genome Immunity In Vitro Induction of Apoptosis Knowledge Link MYC gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolism Methods Modeling Molecular Mutation Non-Small-Cell Lung Carcinoma Outcome Study Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Processes Play Point Mutation Proteasome Inhibition Proteins Radiation therapy Regimen Regulation Relapse Resistance Role Safety Science Testing Tissues Translating Treatment Efficacy c-myc Genes cancer cell cell growth chemotherapy clinical translation combinatorial gene cloning in vivo inhibitor knock-down knockout gene lung cancer cell mutant overexpression pre-clinical research clinical testing resistance mechanism response small molecular inhibitor targeted cancer therapy targeted treatment therapeutic target therapeutically effective transcription factor treatment comparison tumor

项目摘要

SUMMARY An important milestone in the treatment of non-small cell lung cancer (NSCLC) is the discovery of epidermal growth factor receptor (EGFR) activating mutations as an effective therapeutic target and the successful development of EGFR tyrosine kinase inhibitors (EGFR-TKIs). AZD9291 (TAGRISSOTM or osimertinib) represents a 3rd generation EGFR-TKI and an FDA-approved drug for patients with EGFR mutant NSCLC that has become resistant to 1st generation EGFR-TKIs through the T790M mutation and for EGFR mutation-positive advanced NSCLC as a front line treatment. Unfortunately, patients eventually relapse and become resistant to AZD9291 in the clinic, resulting in disease progression. Thus, a better understanding of the underlying mechanisms and development of effective strategies to overcome AZD9291 resistance is an urgent and critical area of unmet need in the clinic. The C-MYC gene was the first Myc family member found in the human genome and its product, c-Myc, functions as a transcription factor to regulate the expression of many genes whose products are involved in the regulation of various physiological processes, such as cell survival, proliferation, differentiation, metabolism and host immunity. MYC is genetically activated and/or overexpressed in most types of human cancer including lung cancer and thus is a central driver of malignant cellular growth and proliferation. c-Myc expression is associated with response or sensitivity of cancer cells to chemotherapy or radiotherapy. However, no study has linked c-Myc to targeted therapy by third generation EGFR-TKIs. Our strong preliminary data support the overall hypothesis that c-Myc modulation may play a critical role in mediating therapeutic efficacy of AZD9291 against EGFRm NSCLC and the development of acquired resistance to AZD9291; accordingly, targeting c-Myc will be an effective strategy to overcome acquired resistance to AZD9291 and other EGFR-TKIs. This hypothesis will be tested by accomplishing the following 3 specific aims: 1) To understand the mechanism(s) by which c-Myc is reduced in EGFR mutant NSCLC cells by AZD9291 or other EGFR-TKIs; 2) To demonstrate the biological significance of c-Myc suppression in EGFR-targeted therapy; and 3) To develop effective therapeutic regimens to overcome acquired resistance to AZD9291 by targeting c-Myc. The objectives of this study are to understand the mechanisms by which AZD9291 and other EGFR-TKIs decrease c-Myc levels, to demonstrate the biological significance of c-Myc suppression during EGFR-targeted cancer therapy; and to develop effective strategies to overcome acquired resistance to AZD9291 by targeting c-Myc. This proposal is of high scientific and translational significance. The outcomes of this study can be immediately translated to the clinical treatment of NSCLC patients with acquired resistance to AZD9291 or other EGFR-TKIs. 1

概括非小细胞肺癌（NSCLC）治疗的重要里程碑是发现表皮生长因子受体（EGFR）激活突变作为有效的治疗靶标和 EGFR酪氨酸激酶抑制剂（EGFR-TKIS）的成功开发。 AZD9291（Tagrissotm或 osimertinib）代表EGFR突变体患者的第三代EGFR-TKI和FDA批准的药物通过T790M突变和EGFR对第一代EGFR-TKI具有抗性的NSCLC 突变阳性晚期NSCLC作为前线处理。不幸的是，患者最终复发在诊所对AZD9291具有抗性，从而导致疾病进展。因此，更好地理解克服AZD9291抵抗的有效策略的基本机制和制定是一种诊所中未满足需求的紧急和关键领域。 C-MYC基因是第一个发现的MYC家庭成员人类基因组及其产物C-MYC充当转录因子，以调节许多产物参与各种生理过程的基因，例如细胞生存，增殖，分化，代谢和宿主免疫。 MYC是基因激活和/或在包括肺癌在内的大多数类型的人类癌症中过表达，因此是恶性肿瘤的中心驱动力细胞生长和增殖。 C-MYC表达与癌细胞对癌细胞的反应或敏感性有关化学疗法或放疗。但是，尚无研究将C-MYC与第三代靶向治疗联系起来 egfr-tkis。我们强大的初步数据支持C-MYC调制可能发挥的总体假设在介导AZD9291对EGFRM NSCLC的治疗功效和发展中的关键作用获得了对AZD9291的抵抗；因此，针对C-MYC将是克服的有效策略获得了对AZD9291和其他EGFR-TKIS的抵抗。该假设将通过完成以下3个具体目的：1）了解EGFR突变体中C-MYC降低的机制 AZD9291或其他EGFR-TKIS的NSCLC细胞； 2）证明C-MYC的生物学意义抑制EGFR靶向疗法； 3）开发有效的治疗方案以克服通过靶向C-Myc获得了对AZD9291的阻力。这项研究的目标是了解 AZD9291和其他EGFR-TKI降低C-MYC水平的机制，以证明生物学 C-MYC抑制在EGFR靶向癌症治疗过程中的重要性；并制定有效的策略通过靶向C-MYC克服对AZD9291的获得的抗性。该提议具有很高的科学性，并且翻译意义。这项研究的结果可以立即转化为对AZD9291或其他EGFR-TKI的NSCLC患者具有抗药性。 1