Targeting Acquired Resistance in KRAS Driven Cancers

针对 KRAS 驱动的癌症的获得性耐药

基本信息

批准号：
10502049
负责人：
Wantong Yao
金额：
$ 44.35万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-12 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10502049
关键词：
Address Area Automobile Driving Biochemical Biological Models Biology Bypass Cancer Model Cancer cell line Cell Culture Techniques Cell Survival Cell membrane Clinical Clinical Trials Colon Colon Carcinoma Colorectal Cancer DNA Sequence Alteration Data Dependence Development Disease Resistance Disease remission Event FDA approved Genetic Transcription Genetically Engineered Mouse Goals HDAC5 gene Human In Vitro KRAS oncogenesis KRAS2 gene Knowledge Laboratories Light Lipid Binding Lipids Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mediating Membrane Mission Modeling Molecular Monoclonal Antibodies Mutate Mutation National Cancer Institute Oncogenes Oncogenic Pathway interactions Patient-Focused Outcomes Patients Pharmacologic Substance Phase Public Health Recovery Regulation Research Resistance Resistance development Role Signal Transduction Surface Testing Therapeutic Therapeutic Effect Therapeutic antibodies Transmembrane Domain Work antitumor effect base cancer therapy cancer type disorder control effective therapy improved in vitro Model in vivo in vivo Model inhibitor innovation knockout gene mutant neoplastic cell new therapeutic target novel novel therapeutic intervention pancreatic cancer model pancreatic cell line pancreatic ductal adenocarcinoma model pre-clinical preclinical evaluation prevent programs recombinase resistance mechanism response success targeted agent targeted cancer therapy targeted treatment therapeutic target therapy development therapy resistant trafficking translatable strategy translational potential treatment response tumor

项目摘要

Development of treatment resistance is a major impediment to effective cancer therapy. KRASG12C inhibitors (KRASi) have been recently approved by FDA and represents a promising new targeted therapy for cancer types with KRAS mutation, one of the most frequent genetic mutations observed in human cancers. However, as is the case with standard therapy, majority of tumors that initially respond to KRASi quickly develop resistant disease. Unfortunately, the underlying mechanisms of KRASi resistance are poorly understood. To tackle this challenging problem, this application will capitalize on the PI's track record and expertise in the area of KRAS signaling and biology and propose a comprehensive research program focusing on understanding the mechanisms of acquired resistance to KRAS targeted therapy. This application will identify new actionable therapeutic targets and approaches to overcome resistance, thus greatly improving the clinical outcome of patients with KRAS mutated cancers. To achieve this, the Yao laboratory has developed in vitro and in vivo model systems that will be employed to investigate hypotheses regarding mechanisms driving the development of KRASi resistance. The in vitro model system consists of KRAS dependent and independent cell cultures derived from genetically engineered mouse models of pancreatic cancer as well as human cancer cell lines of pancreatic and colon origin. The in vivo model system consists of patient-derived colon cancer models that developed resistance to KRASi, as well as genetically engineered mouse models of pancreatic cancer driven by KRASG12C. The major knowledge gaps to be addressed are that: i) what molecular events are activated to enable bypass of KRAS dependency in tumors treated with KRASi; ii) how these molecular events function to drive tumor survival and maintenance in response to KRASi; and iii) whether pharmaceutically targeting the resistant mechanism can achieve durable therapeutic responses in combination with KRASi. These studies will unveil a previously unknown mechanism by which tumor cells become resistant to KRAS targeted therapy and may define an innovative therapeutic option for KRASi-resistant patients. The proposed work comprises an essential step toward our long-term goal of developing effective therapy for patients with KRAS mutated cancer, in align with the mission of the National Cancer Institute (NCI) RAS initiative (“Kill RAS”).

治疗耐药性的产生是 KRASG12C 抑制剂有效治疗的主要障碍。 (KRASi) 最近已获得 FDA 批准，代表了一种有前景的针对癌症类型的新型靶向疗法 KRAS 突变是人类癌症中最常见的基因突变之一。在标准治疗的情况下，大多数最初对 KRASi 产生反应的肿瘤很快就会产生耐药性不幸的是，人们对 KRASi 耐药的潜在机制知之甚少。具有挑战性的问题，该应用程序将利用 PI 在 KRAS 领域的跟踪记录和专业知识信号和生物学，并提出一个全面的研究计划，重点是了解 KRAS 靶向治疗的获得性耐药机制该应用将确定新的可操作的方法。克服耐药性的治疗靶点和方法，从而大大改善临床结果为了实现这一目标，姚实验室在体外和体内进行了开发。将用于研究有关驱动发展机制的假设的模型系统 KRASi 耐药性的体外模型系统由 KRAS 依赖性和独立细胞培养物组成。源自胰腺癌基因工程小鼠模型以及人类癌细胞系胰腺癌和结肠癌的体内模型系统由源自患者的结肠癌模型组成。开发出对 KRASi 的耐药性，以及由基因工程驱动的胰腺癌小鼠模型 KRASG12C。要解决的主要知识差距是：i）激活哪些分子事件以实现绕过 KRASi 治疗的肿瘤中的 KRAS 依赖性；ii) 这些分子事件如何发挥驱动作用；响应 KRASi 的肿瘤存活和维持；以及 iii) 是否在药物上靶向耐药性这些研究将揭示一种与 KRASi 相结合的机制可以实现持久的治疗反应。以前未知的肿瘤细胞对 KRAS 靶向治疗产生耐药性的机制可能为 KRASi 耐药患者定义一种创新的治疗方案。拟议的工作包括一项重要内容。朝着我们为 KRAS 突变癌症患者开发有效疗法的长期目标迈出了一步，肩负着美国国家癌症研究所 (NCI) RAS 计划（“杀死 RAS”）的使命。