Predicting sensitivity and resistance in RET-driven cancers

预测 RET 驱动的癌症的敏感性和耐药性

• 批准号: 10376881
• 负责人: Alexander Drilon
• 金额: $ 39.68万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376881
• 关键词: Address; Adoption; Adult; Allelic Imbalance; Biological; Biopsy; Bypass; Cataloging; Clinical; Clonality; Collection; Combined Modality Therapy; Computer Analysis; Computing Methodologies; Data Set; Dependence; Drug Approval; Effectiveness; Evolution; FDA approved; Future; Genetic; Genomics; Histologic; In Vitro; KRAS2 gene; Kinetics; Leadership; Lesion; Libraries; Life; Lung; MDM2 gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of thyroid; Methods; Modeling; Molecular; Mutation; Nature; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Pharmacology; Phase I/II Trial; Plasma; Pre-Clinical Model; Progression-Free Survivals; Protocols documentation; RET inhibition; Receptor Protein-Tyrosine Kinases; Resistance; Resistance development; Resources; Role; Sampling; Savings; Signal Transduction; Therapeutic; Time; Tissues; Treatment Efficacy; Tyrosine Kinase Inhibitor; Validation; cell free DNA; clinically relevant; co-clinical trial; combinatorial; deep sequencing; disorder control; exome sequencing; in vivo; inhibitor; inhibitor therapy; model development; mutant; neoplastic cell; next generation; non-genomic; novel; novel therapeutic intervention; patient biomarkers; patient derived xenograft model; pre-clinical; prevent; programs; prospective; resistance mechanism; responders and non-responders; response; tumor; tumor progression

Selpercatinib (LOXO-292) is a highly active selective RET inhibitor explored on an ongoing registrational program (LIBRETTO-001 phase 1/2 trial) in RET-dependent cancers (US FDA approval in 2020 for RET fusion-positive lung/thyroid cancer and RET-mutant thyroid cancer). Unfortunately, resistance is uncharacterized and remains a liability. This proposal anticipates and addresses this unmet need by identifying and functionally characterizing mechanisms of intrinsic and acquired genomic and non-genomic resistance to selective RET inhibition in RET-dependent cancers. To accomplish this, we will leverage unique clinical, computational, and translational resources at our disposal. Aim 1 will identify determinants of intrinsic resistance to RET inhibition in RET-dependent cancers. Pre-treatment biopsies of selpercatinib responders and non-responders will undergo targeted/whole exome sequencing. Computational analysis will explore the role of clonality, allelic imbalance, and co-mutational signatures relative to selpercatinib response and progression-free survival. Aim 2 will establish the mechanisms of acquired resistance to selective RET inhibition. Paired pre-treatment and post-progression tumor biopsies and longitudinal cell-free (cf)DNA (baseline, on-treatment, at/post- progression) from LIBRETTO-001 patients will be profiled. Utilizing paired samples will allow for the identification of emergent genomic and non-genomic (including histologic/EMT transformation) resistance mechanisms. In addition, plasma profiling will allow for a dynamic assessment of selpercatinib resistance that captures the consequences of serial genomic evolution. Aim 3 will functionally characterize resistance to selective RET inhibition. A unique and rich library of patient-derived models of treatment-naïve and RET inhibitor resistant RET-dependent cancers will be augmented by ongoing prospective collection and model development from LIBRETTO-001 and commercial use. In these models, on-target (secondary RET mutations) and off-target (MET/PI3K/KRAS/MDM2 activation) resistance mechanisms will be functionally characterized in terms of cell/tumor viability, receptor tyrosine kinase activation, and downstream signaling dependencies. Novel therapeutic strategies, specifically RET tyrosine kinase inhibitor type switching (on-target resistance) and combinatorial therapies (off-target resistance), will be explored in vitro and in vivo. Optimal combination therapies will then be employed in compassionate use programs to confirm their effectiveness and provide tailored, life-saving treatment to patients. In addition, patients with on-target resistance will be treated on-protocol (Drilon PI) with the next-generation RET inhibitor, TPX-0046. This proposal has both immediate and long-term relevance considering that about 400 patients have been treated with selpercatinib around the world on trial and the potential approval and rapid adoption of this drug by multiple regulatory agencies. These current and future patients are in dire need of strategies to re-establish durable disease control after progression on selective RET inhibition.

Selpercatinib（LoxO-292）是在正在进行的注册中探索的高度活跃的选择性RET抑制剂 RET依赖性癌症中的程序（Libretto-001阶段1/2试验）（2020年美国FDA批准为RET 融合阳性肺/甲状腺癌和甲状腺癌癌）。不幸的是，抵抗是 未经表征，仍然是责任。该提案可以通过识别来预测并解决这种未满足的需求 并在功能上表征内在和获得的基因组和非基因组抗性的机制 选择性RET抑制作用依赖性癌症。为此，我们将利用独特的临床， 计算和翻译资源可以使用。 AIM 1将确定固有的决定者 抗RET依赖性癌症的RET抑制作用。选择性响应者的预处理活检 并且非反应者将进行目标/整个外显子组测序。计算分析将探索 克隆性，艾里克失衡和相对于selectercatinib响应的共同签名的作用 无进展生存。 AIM 2将建立获得选择性RET的抗性的机制 抑制。配对的预处理和后期后的肿瘤活检和纵向细胞（CF）DNA （基线，治疗，AT/AT/进展后）将介绍Libretto-001患者。利用配对 样品将允许鉴定出现的基因组和非基因组（包括组织学/EMT 转化）抵抗机制。此外，血浆分析将允许对 捕获序列基因组进化的后果的选择catinib抗性。 AIM 3将在功能上 表征对选择性RET抑制的抗性。一个独特而丰富的患者衍生模型库 持续的前瞻性将增强治疗的不接受治疗和RET抑制剂抗性RET依赖性癌症 Libretto-001和商业用途的收集和模型开发。在这些模型中，目标 （次级RET突变）和脱靶（MET/PI3K/KRAS/MDM2激活）电阻机制将是 在功能上以细胞/肿瘤活力，受体酪氨酸激酶激活和下游来表征 信号依赖性。新型的热策略，特别是RET酪氨酸激酶抑制剂类型开关 （靶向抗性）和组合疗法（脱靶耐药性）将在体外和体内进行探索。 然后，将在富有同情心的程序中聘请最佳组合疗法以确认其 有效性并为患者提供量身定制的救生治疗。此外，靶向的患者 电阻将与下一代RET抑制剂TPX-0046一起在业务上（Drilon PI）处理。这 考虑到约有400名患者已接受治疗，提案具有立即和长期相关性 在世界各地的SmartCatinib审判以及潜在的批准和迅速采用这种药物 多个监管机构。这些当前和未来的患者迫切需要重新建立的策略 选择性RET抑制后进展后持久的疾病控制。