Extending experimental evolutionary game theory in cancer in vivo to enable clinical translation: integrating spatio-temporal dynamics using mathematical modeling

扩展癌症体内实验进化博弈论以实现临床转化：使用数学建模整合时空动力学

• 批准号: 10662098
• 负责人: Andriy Marusyk
• 金额: $ 55.8万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662098
• 关键词: 3-Dimensional; Address; Antibiotic Resistance; Automobile Driving; Biological; Biological Assay; Biological Process; Biology; Cancer Model; Clinic; Clinical; Clinical Medicine; Clinical Trials; Code; Communities; Complex; Computer Models; Data; Disease; Ecosystem; Epidermal Growth Factor Receptor; Evolution; Exhibits; Extinction; Favorable Clinical Outcome; Fisheries; Game Theory; Generations; Genes; Glean; Grain; Growth; Heterogeneity; In Vitro; Intuition; Life; Literature; Malignant Neoplasms; Malignant neoplasm of prostate; Mathematics; Measurement; Measures; Methods; Modeling; Mutation; New Agents; Non-Small-Cell Lung Carcinoma; Patients; Pesticides; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Population; Population Heterogeneity; Pre-Clinical Model; Process; Protein Tyrosine Kinase; Proteins; Qualitative Methods; Race; Refractory; Relapse; Research; Resistance; Role; System; Testing; Theoretical Studies; Theoretical model; Therapeutic; Therapeutic Intervention; Time; Translating; Tyrosine Kinase Inhibitor; Work; abiraterone; actionable mutation; anticancer research; cancer therapy; clinical translation; clinically relevant; design; experience; in silico; in vitro Model; in vivo; inhibitor; insight; interdisciplinary approach; invention; mathematical model; multi-scale modeling; mutant; neoplastic cell; next generation; novel; pathogen; physical science; pressure; response; spatiotemporal; success; targeted cancer therapy; targeted treatment; theories; therapy design; tool; trial design; tumor; two-dimensional

ABSTRACT Targeted cancer therapy, in the form of tyrosine kinase inhibitors, has been a game changer for patients with cancers driven by activating mutations in genes encoding these proteins. Yet, while we are seeing overall survival benefits unlike with any new agents in over a decade, cures remain elusive, or non-existent, as resistance to these agents reliably emerges. The process driving this resistance is the same process that drives invasive pests' resistance to pesticides, pathogens' resistance to antibiotics and many other phenomena in life: Darwinian evolution. While this is being increasingly recognized, it has yet to change the paradigm in cancer research where most projects are centered on a hunt for actionable mutations conferring resistance. While these secondary mutations are often druggable themselves, we submit that this is a never-ending race that evolution will always win. We hypothesize that an approach centered instead on studying the evolutionary process itself can help break this cycle. While there is a robust theoretical literature modeling cancer evolution with mathematics, there is a relative paucity of research connecting this theory to empirical biology or clinical medicine. To address this shortcoming, we have worked for the past three years to develop a first-in-class evolutionary game assay to directly measure the eco-evolutionary interactions driving the emergence of resistance in vitro. This assay allows us to directly parameterize an evolutionary game theoretic model with empiric studies in any system. Here, we propose to extend our initial observations revealing a vast heterogeneity in evolutionary dynamics under different agents in vitro to allow for clinical translation by extend ouring assay to an in vivo system. We posit that the new methods and understanding we will gain during this proposal will benefit the cancer research community as a whole, as well as provide novel opportunities for therapeutic interventions aimed at disrupting and altering the evolutionary mechanisms driving resistance.

抽象的 以酪氨酸激酶抑制剂的形式，有针对性的癌症治疗已成为患者的游戏规则改变者 通过在编码这些蛋白质的基因中激活突变驱动的癌症。然而，虽然我们正在寻找总体生存 与十多年来的任何新代理商不同，好处是难以捉摸或不存在的治疗 这些代理商可靠地出现。驱动这种阻力的过程与驱动侵入性的过程相同 害虫对农药的抵抗力，病原体对抗生素的抵抗力以及生活中许多其他现象：达尔文人 进化。虽然越来越多地认识到这一点，但它尚未改变癌症研究中的范式 大多数项目集中在寻找可操作的突变会议阻力上。而这些次要 突变本身通常是可以吸毒的，我们认为这是一场永无止境的种族，进化将永远 赢。我们假设一种以研究进化过程本身为中心的方法可以帮助 打破这个周期。虽然有一个强大的理论文献用数学建模癌症的演变，但 是将该理论与经验生物学或临床医学联系起来的研究相对缺乏的。解决这个问题 缺点，我们在过去三年中一直在工作，以开发第一类进化游戏测定法 直接测量驱动体外抗性出现的生态进化相互作用。此测定允许 我们可以通过任何系统中的经验研究直接对进化游戏理论模型进行参数化。在这里，我们 扩展我们最初观察的提议揭示了不同的进化动力学异质性 体外的代理通过将我们的评估扩展到体内系统，以允许进行临床翻译。我们指出新的 我们将在本提案中获得的方法和理解将使癌症研究界有益于 整体，以及为旨在破坏和改变的治疗干预措施提供新的机会 进化机制驱动抗性。