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

摘要 以酪氨酸激酶抑制剂为形式的靶向癌症治疗已经改变了患有癌症的患者的游戏规则 由编码这些蛋白质的基因的激活突变所驱动的癌症。然而，当我们看到总体存活率 与十多年来任何新的药物不同，Benefi的治疗方法仍然难以捉摸，或者根本不存在，因为对 这些特工可靠地出现了。驱动这种抵抗的过程与驱动入侵的过程是相同的 害虫对杀虫剂的抗药性，病原体对抗生素的抗药性和生活中的许多其他现象：达尔文主义 进化论。虽然这一点越来越被认识到，但它还没有改变癌症研究的范式 大多数项目都集中在寻找可能导致耐药性的可操作突变。而这些次要的 突变本身往往是可以下药的，我们认为这是一种永无止境的种族，进化将永远 赢。我们假设，以研究进化过程本身为中心的方法可能会有所帮助 打破这个循环。虽然有强有力的理论文献用数学来模拟癌症的进化，但 将这一理论与经验生物学或临床医学联系起来的研究相对较少。要解决这个问题 缺点，我们在过去的三年里一直致力于开发一个fi第一流的进化博弈分析来 在体外直接测量驱动抗性产生的生态进化相互作用。这种化验方法允许 我们可以在任何系统中通过经验研究直接将进化博弈论模型参数化。在这里，我们 建议扩展我们最初的观察，揭示在不同的 通过将OUR试验扩展到体内系统，允许临床翻译的体外试剂。我们假设新的 我们在这项提案中获得的方法和理解将使fi癌症研究界作为一个 整体上，以及为旨在扰乱和改变 驱动抗药性的进化机制。

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.