Unmasking targetable dependencies in cancer with intrinsic or acquired resistance to anti-cancer therapies

揭示癌症中对抗癌疗法具有内在或获得性耐药性的靶向依赖性

基本信息

批准号：
9814740
负责人：
Grace R Anderson
金额：
$ 7.16万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2019-08-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9814740
关键词：
Address Antibiotic Resistance Antibiotics Apoptosis Apoptotic Architecture Area BCL1 Oncogene BCL2 gene Bacteria Bypass CRISPR/Cas technology Cell Death Cell Survival Cell physiology Cells Clinical Clinical Research Clinical Trials Combined Modality Therapy Complex Coupled Dependence Disease Drug resistance Effectiveness Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor FRAP1 gene Family Follow-Up Studies Future Genes Genetic Screening Genetic study Genomic approach Goals Growth Heterogeneity Hypersensitivity Immunologics KRAS2 gene Knowledge Lead MCL1 gene MEK inhibition Malignant Neoplasms Malignant neoplasm of lung Manuscripts Modeling Mutation Oncogenes Oncogenic Outcome PIK3CA gene Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacology Study Positioning Attribute Process Proteins Relapse Reporting Research Research Personnel Research Project Grants Resistance Resistance development Signal Pathway Signal Transduction Solid Neoplasm Technology Therapeutic Tissues Translational Research Universities Work base cancer cell cancer genomics cancer subtypes cancer therapy cancer type cell growth combinatorial design fighting fitness follow-up functional genomics genomic tools improved inhibitor/antagonist insight interest loss of function malignant breast neoplasm microbial mimetics mutant mutational status neoplastic cell novel oncogene addiction resistance mechanism response screening skills small molecule inhibitor synthetic biology targeted treatment therapeutic target tool translational medicine tumor

项目摘要

Abstract: Cancer is a complex disease characterized by the deregulation of normally balanced cell growth and survival pathways. Mutational alteration of specific oncogenes, such as PIK3CA and KRAS, can lead cancer cells to become dependent on their associated signaling pathways, a process known as oncogene addiction. As such, there has been a focused effort to develop inhibitors of major oncogenic pathways in cancer with the hypothesis that these drugs will cause tumor-specific cell death, ultimately leading to better outcomes in patients. However, intrinsic and acquired resistance to these so-called “targeted therapies”, which is often driven by the activation of compensatory, or bypass, signaling mechanisms, limits their effectiveness by blocking drug- induced apoptosis (cell death). On the basis of these concepts, we hypothesized that we could improve the activity of targeted therapies by systematically identifying the pathways that drive resistance using high-throughput functional genomics approaches, coupled with mechanistic follow-up studies, and then leverage these insights to define combination therapies that drive potent and tumor-selective cell death. This project aims to characterize new dependencies, deemed “collateral sensitivities”, in cancers that evolved resistance to a primary drug because these may be interesting therapeutic targets for patients that have already relapsed on a given targeted therapy. Collateral sensitivity is a concept that has been explored in detail in the microbial world. It is well established that once a bacterium becomes resistant to a given antibiotic, that bacterium often becomes hypersensitive to new antibiotics to which it was previously insensitive (collateral sensitivity). Reciprocally, that bacterium can also become resistant certain antibiotics to which it was previously sensitive (collateral resistance). There are many parallels between the fields of antibiotic resistance and resistance to targeted therapies in cancer; however, despite its potential clinical impact, there have not been any systematic efforts to study collateral sensitivity/resistance in diverse cancers.

摘要：癌症是一种复杂的疾病，其特征是正常平衡失调。特定癌基因（例如 PIK3CA）的突变改变。和 KRAS，可以导致癌细胞变得依赖于其相关的信号通路，一个被称为癌基因成瘾的过程因此，人们一直在努力开发。癌症主要致癌途径的抑制剂，假设这些药物会导致肿瘤特异性细胞死亡，最终为患者带来更好的结果。对这些所谓的“靶向治疗”产生耐药性，这通常是由激活引起的补偿性或旁路信号机制通过阻断药物来限制其有效性诱导细胞凋亡（细胞死亡）在这些概念的基础上，我们进化出我们可以。通过系统地识别驱动途径来提高靶向治疗的活性使用高通量功能基因组学方法结合机制来对抗耐药性后续研究，然后利用这些见解来定义驱动的联合疗法该项目旨在表征新的依赖性，被认为是“附带敏感性”，因为癌症对主要药物产生了耐药性，因为对于已经在特定时间复发的患者来说，这些可能是有趣的治疗目标靶向治疗是一个在微生物学中已被详细探讨的概念。众所周知，一旦细菌对某种抗生素产生抗药性，就会产生耐药性。细菌常常对以前不敏感的新抗生素变得过敏（附带敏感性）。相反，该细菌也会对某些抗生素产生耐药性。它以前对此很敏感（附带阻力），两者之间有许多相似之处。然而，尽管存在抗生素耐药性和癌症靶向治疗耐药性等领域；潜在的临床影响，目前还没有任何系统性的努力来研究抵押品不同癌症的敏感性/耐药性。