Cancer Biology & Evolution

项目摘要 癌症生物学与进化 癌症生物学与进化（CBE）计划的重点是了解肿瘤的发生，进展， 从进化的角度来看，转移和耐药性。CBE研究是在界面上进行的 分子癌症生物学，转化研究和数学建模，重点是优先癌症 在莫菲特的集水区这个创新的项目源于我们认识到癌症是复杂的， 多尺度、开放的动态系统鉴于打击这种现象需要采取跨学科办法， 复杂性，数学家，计算机科学家，癌症生物学家和临床医生被招募到CBE， 挑战长期以来的信念，即"癌症太复杂，无法建模"，值得注意的是，CBE采用了 进化是控制癌症生物学各个方面以及对治疗反应的中心驱动力。 虽然CBE支持传统的发现生物医学研究，成功地定义了新的途径， CBE是促进癌症发展、进展和转移的效应物， 将这些数据转化为围绕进化第一原理组织的理论框架， 复杂的数学模型因此，CBE的首要目标是定义复杂的多方面的， 通过进化的透镜控制癌症的生物学和治疗反应的尺度动力学，以及 提供新的药物和策略，用于预防和治疗转移性、难治性或复发性 恶性肿瘤。为了实现其目标，CBE研究分为三个具体目标： 目标1：定义在癌症发展和进展中起作用的网络。 目的2：建立人类肿瘤发生、发展、转移的动物模型和数学模型 和治疗抗性。 目标3：将基本发现转化为个性化的模型疗法。 CBE自2012年成立以来蓬勃发展，多学科团队推动了主要的科学研究， 在癌症生物学、进化、数学建模和临床研究的界面上取得进展。这 一个强大的资金组合，包括19个多PI赠款（U54，T32和8 U01）和第一个， 适应性治疗的实物临床试验，在难治性和转移性疾病中显示出显着的益处。 此外，已经出现了两个P01申请未决的研究团队，他们专注于确定 肺癌的代谢脆弱性和发展癌症的进化疗法。37 CBE 成员有23个以癌症为重点的R01赠款等价物，960万美元的年度赠款直接成本（740万美元的同行， 自2016年以来，共发表了656篇论文。CBE未来的优先事项是使用最先进的GEMM， 数学建模和机器学习来解卷积癌细胞-内在和外在控制 癌症进展、转移和治疗耐药性中的信号传导和代谢回路，并促进 推出新的同类适应性治疗临床试验，降低癌症发病率并改善结果。

PROJECT SUMMARY CANCER BIOLOGY & EVOLUTION PROGRAM The Cancer Biology & Evolution (CBE) Program is focused on understanding tumor initiation, progression, metastasis and therapy resistance from an evolutionary perspective. CBE research is conducted at the interface of molecular cancer biology, translational research and mathematical modeling with a focus on priority cancers in Moffitt’s catchment area. This innovative Program emerged from our recognition that cancers are complex, multi-scale, and open dynamic systems. Given the interdisciplinary approaches required to combat such complexity, mathematicians, computer scientists, cancer biologists, and clinicians were recruited to CBE to challenge the long-held belief that “cancer is too complicated to model,” Notably, CBE adopted the principles of evolution as a central driver that governs all aspects of cancer biology as well as the response to therapies. While CBE supports traditional discovery biomedical studies that have successfully defined new pathways and effectors that contribute to the development, progression and metastasis of cancer, CBE uniquely integrates these data into theoretical frameworks organized around evolutionary first principles that are facilitated by sophisticated mathematical models. Accordingly, the overarching goals of CBE are to define the complex multi- scale dynamics that govern the biology and therapeutic responses of cancer through the lens of evolution, and to deliver new agents and strategies for the prevention and treatment of metastatic, refractory or relapsed malignancies. To achieve its goals, CBE research is organized into three Specific Aims: Aim 1: To define networks operational in cancer development and progression. Aim 2: To develop animal and mathematical models of human cancer development, progression, metastasis and therapeutic resistance. Aim 3: To translate basic discoveries into personalized modeled therapies. CBE has flourished since its inception in 2012, where multidisciplinary teams have driven major scientific advances at the interface of cancer biology, evolution, mathematical modeling and clinical research. This success is underscored by a robust funding portfolio including 19 multi-PI grants (U54, T32, & 8 U01s) and first- in-kind Adaptive Therapy clinical trials that have shown remarkable benefit in refractory and metastatic disease. In addition, two research teams with pending P01 applications have emerged that are focused on identifying metabolic vulnerabilities in lung cancer and developing evolutionary therapy for cancer. Together, the 37 CBE Members have 23 cancer-focused R01 grant equivalents, $9.6M in annual grant direct costs ($7.4M peer- reviewed), and 656 publications since 2016. Future priorities of CBE are to use state-of-the-art GEMM, mathematical modeling, and machine learning to deconvolute cancer cell-intrinsic and extrinsic control of signaling and metabolic circuits in the progression, metastasis, and therapy resistance of cancer, and to foster the rollout of new first-in-kind adaptive therapy clinical trials that reduce cancer morbidity and improve outcomes.