Defining the universal genomic language of hallmarks in tumor development

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PROJECT SUMMARY Genomic changes are a universal and near inevitable cause of tumor development. The field has focused mostly on tumors that rely on singular “driver” mutations to proliferate, and these insights have inspired driver-directed therapies that provide effective clinical options for ~20% of patients. However, most genomes are more complex, harboring hundreds of somatic mutations without a single “druggable” driver. Comprehensive discovery of tumor- promoting mechanisms in these complex genomes would broadly impact genome-inspired drug discoveries for millions of patients. This New Innovator Award project represents a creative paradigm shift beyond individual drivers – by discovering “genomic programs” of multiple coordinated mutations that interact and activate essential hallmarks in tumor development (e.g., uncontrolled proliferation, deregulated metabolism, genome instability, angiogenesis, immune evasion, and metastasis). This innovative, cutting-edge technology will uniquely combine the discovery potential of unsupervised machine learning, the information value of leading statistical approaches, and data from genomics, epigenomics, radiology, pathology, pharmacology, transcriptomics, proteomics, CRISPR, and cell biology. Genomic programs will elucidate essential mechanisms in tumor development beyond singular driver mutations, which include: 1) Activation of genomic regulatory elements to unleash cancer gene expression. 2) Tumor-specific epigenomic structures to control tumor signaling. 3) Mechanisms in tumor evolution to select precancer lesions. 4) Interactions that enable tumors to adapt and survive in metastatic environments. Identifying the shared underlying cause of these mechanisms will overcome the biases of field-specific approaches and define interactions of coordinated processes in tumor development. The proposed research is conceptually innovative as it pivots precision medicine toward identifying genome- inspired drug targets beyond drivers. It also introduces numerous technological innovations to identify complex structures in radiogenomics, pharmacogenomics, noncoding genomes, organotropism, tumor evolution, epigenomics, regulatomes, and interactomes. It comes at a pivotal time since many whole cancer genomes became available only recently, emphasizing their potential to produce an unusually high impact in a short period of time. Moreover, this proposal fundamentally differs from traditional research grants in its ambitious scope, broad applicability, integration of data and technologies from diverse disciplines, and a creative leap in research trajectory. In sum, this high-risk, high-reward project will create an innovative technology universally applicable to the genomes of all cancer types. It will generate fundamental knowledge to advance driver-directed monotherapies toward hallmark-directed combination therapies with the ultimate potential to produce more durable responses in millions of patients. Its impact extends beyond cancer, including age-associated diseases in neurology, cardiology, and nephrology that are driven by similar genomic principles.