A Convergent Node in Melanoma to Block Multiple Oncogenic Pathways Simultaneously

黑色素瘤中的汇聚节点可同时阻断多种致癌途径

• 批准号: 10431861
• 负责人: Lawrence Kwong
• 金额: $ 49.58万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10431861
• 关键词: Address; BRAF gene; Bioinformatics; Biological Models; Biopsy; CDK4 gene; Cancer Model; Cell Cycle; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cell model; Cellular Metabolic Process; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Data; Development; Drug Controls; Drug Design; Drug Targeting; Drug resistance; FRAP1 gene; Foundations; Future; Genes; Genetic; Goals; Human; Immunohistochemistry; Link; MAP Kinase Gene; MEKs; Mediating; Melanoma Cell; Metabolic; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Mutation; NF1 mutation; Oncogenic; Outcome; PIK3CA gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Proteomics; Quality of life; Recording of previous events; Resistance; Ribosomal Protein S6 Kinase; Role; Sampling; Series; Signal Transduction; Testing; Therapeutic; Therapeutic Uses; Toxic effect; Treatment Efficacy; cell growth; clinical application; clinically relevant; clinically significant; design; drug testing; improved; in vivo; inhibitor; inhibitor therapy; knock-down; melanocyte; melanoma; melanomagenesis; mouse model; mutant; next generation; novel; pre-clinical; prevent; resistance mechanism; targeted treatment; therapeutic target; tumor initiation; tumorigenesis

ABSTRACT Despite recent major advances in targeted therapy for melanoma, the nearly universal eventual acquisition of drug resistance remains a major hurdle that prevents durable gains in patient survival. To address this critical unmet need, we have recently used patient samples and model systems to identify S6K1 as a critical counter-resistance therapy target that lies at the downstream convergence point of the MAPK, CDK4/6, and PI3K pathways. Importantly, these are the primary drivers of both melanomagenesis and of known BRAF and MEK inhibitor resistance mechanisms, positing S6K1, an understudied drug target, as a potential broad-use salvage and/or frontline therapy. Our preliminary data is consistent with this hypothesis, as pharmacological S6K1 inhibition reversed MAPK inhibitor resistance in several drug and genetic contexts. Our central hypothesis is that understanding the mechanistic basis and clinical applicability of S6K1 inhibition in melanoma will allow for improved design of next-generation S6K1 inhibitors and combination therapies, as well as a deeper functional understanding of drug resistance mechanisms operating through and downstream of S6K1. Specific Aim 1 will focus on developing S6K1 as a key drug target in the contexts of both drug resistance and tumor initiation, and its clinical relevance will be interrogated in a series of clinical biopsies. Specific Aim 2 will determine the oncogenic mechanisms downstream of S6K1, with distinct focuses on its impact on cell cycle and metabolism. Overall, successful completion of this study will provide an evidential basis for S6K1 as a promising broad-use therapeutic target, with a mechanistic underpinning to further refine future designs and uses of pharmacological S6K inhibitors.

摘要 尽管最近在黑色素瘤的靶向治疗方面取得了重大进展，但几乎普遍的最终 获得耐药性仍然是阻碍患者获得持久进展的主要障碍 生死存亡。为了解决这一关键的未得到满足的需求，我们最近使用了患者样本和模型 将S6K1识别为关键的抗耐药治疗靶点的系统 MAPK、CDK4/6和PI3K通路的下游汇聚点。重要的是，这些 是黑色素瘤发生和已知的BRAF和MEK抑制剂的主要驱动因素 耐药机制，认为S6K1，一个未被研究的药物靶点，可能被广泛使用 抢救和/或一线治疗。我们的初步数据与这一假设一致，因为 药物抑制S6K1逆转几种药物和基因对MAPK抑制剂的耐药性 上下文。我们的中心假设是理解机制基础和临床 S6K1抑制在黑色素瘤中的适用性将允许改进下一代设计 S6K1抑制剂和联合疗法，以及对药物更深入的功能理解 通过S6K1和S6K1下游的抗性机制。具体目标1将专注于 S6K1在耐药和肿瘤背景下作为关键药物靶点的研究 它的临床相关性将在一系列临床活组织检查中被询问。特定的 目标2将确定S6K1下游的致癌机制，重点不同于 它对细胞周期和代谢的影响。总体而言，这项研究的成功完成将提供 S6K1作为一种有前景的广泛使用的治疗靶点的证据基础和机制 为进一步完善药物性S6K抑制剂的未来设计和用途奠定了基础。