Cancer Biology & Evolution

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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.