Cancer Evolution and Combinatorial Cancer Therapies: Concepts and Challenges

摘要 要求为题为“癌症演变和组合治疗”的Keystone专题讨论会提供支助。 癌症治疗：概念和挑战，由William Sellers，Charles萨旺德和Lillian博士组织 萧会议将于2020年1月19日至23日在加拿大阿尔伯塔省班夫举行。 在理解克隆和亚克隆过程驱动肿瘤演变、肿瘤异质性、 治疗抗性的机制，以及在定义新的癌症依赖性方面， 为实现变革性联合治疗的发展提供更合理的方法 治疗癌症的方法尽管如此，高度有效的合理阐明的组合的例子仍然很少 并且对该目标的临床前和临床开发挑战是巨大的。为例 具有治疗潜力的免疫治疗剂的新兴作用已经引起了巨大的兴奋，然而， 增加了复杂性。广泛的基于经验的临床试验证明了 需要改进的临床前手段，通过该手段可以鉴定转化性组合。 这次会议将汇集进化和计算生物学家，功能基因组学专家， 翻译科学家、药物发现研究人员和临床开发领域的医生领导者。的 会议计划从进化过程如何驱动癌症的“自然”进展以及如何 这样的过程导致测量的异质细胞群驻留在所有肿瘤中。这两 相关的力量，至少部分地由正在进行的突变过程驱动，然后联合收割机结合起来，产生治疗效果。 耐药性，使研究人员能够在临床前研究中稳健地确定与人类相关的机制。 模型对这些力量的更深入理解可以为特定的联合疗法提供信息， 通过基因组规模的功能筛选方法， (e.g. CRISPR、shRNA）。发言者被邀请讨论目前正在进行的研究， 靶向和免疫肿瘤学（I/O）治疗领域。这些谈话渗透到理解的会议中 I/O和靶向治疗如何相似或不同，并从临床试验输出中寻求经验教训， I/O领域将在明年出现。最后，临床开发范式可以更快地 会议期间将讨论测试和开发组合的问题。

ABSTRACT Support is requested for a Keystone Symposia conference entitled Cancer Evolution and Combinatorial Cancer Therapies: Concepts and Challenges, organized by Drs. William Sellers, Charles Swanton and Lillian Siu. The conference will be held in Banff, Alberta Canada from January 19-23, 2020. Progress in understanding the clonal and sub-clonal processes driving tumor evolution, tumor heterogeneity, the mechanisms of therapeutic resistance, and in defining new cancer dependencies have converged to help inform more rational approaches to achieving the development of transformative combination therapeutic regimens in cancer. Nonetheless, examples of highly effective rationally elucidated combinations remain rare and the pre-clinical and clinical development challenges to this goal are substantial. As an example, the emergent role of immunotherapeutics having curative potential has led to tremendous excitement, yet increased complexity. The broad swath of empiric based clinical trials attests to the continued and growing need for improved pre-clinical means by which transformative combinations can be identified. This conference will bring together evolutionary and computational biologists, experts in functional genomics, translational scientists, drug discovery researchers and physician leaders in clinical development. The conference program begins with how evolutionary processes drive the “natural” progression of cancer and how such processes lead to the measured heterogeneous populations of cells resident in all tumors. These two related forces, driven at least in part by ongoing mutational processes, then combine to give rise to therapeutic resistance, which enables researchers to robustly identify mechanisms relevant to humans in pre-clinical models. The deeper understanding of these forces can inform specific combination therapeutics, but combination hypotheses are now being discovered though genome-scale functional screening approaches (e.g. CRISPR, shRNA). Speakers have been invited to discuss the studies which are now taking place in both the targeted and immuno-oncology (I/O) therapeutic fields. These talks filter into sessions on understanding how I/O and targeted therapeutics are similar or distinct and to seek the lessons from the clinical trial outputs in the I/O field that will emerge over the next year. Finally, clinical development paradigms for more rapidly testing and developing combinations will be covered during the conference.