PRECISION ONCOLOGY AND SYSTEMS BIOLOGY PROGRAM: SUMMARY Cancer is an increasingly complex and dynamic disease, requiring equally complex and multidisciplinary solutions implemented by transdisciplinary investigator teams. The Precision Oncology and Systems Biology (POSB) Program seeks to address this challenge by developing innovative, quantitative, multi-omics models and by leveraging molecular- and image-based biomarkers for their translation to the clinic. Under the co-leadership of Andrea Califano, Dr. Chair of Systems Biology and Richard Carvajal MD, Director of Phase 1 Experimental Therapeutics and Director of Melanoma Service, the POSB Program comprises 40 Members from four basic sciences and seven clinical departments, as well as biomedical engineering, across three schools at Columbia University. During the project period, the Aims of the POSB Program - previously called the Cancer Regulatory Network (CRN) Program - were further focused towards leveraging innovative, model-based methodologies and technologies to implement a precision oncology framework vital to effective clinical translation. POSB Members implement quantitative methodologies for the effective prioritization of patient-specific treatments by integrating both emergent cancer systems biology approaches and mainstream strategies. As a result, the POSB Program’s interrelated Specific Aims revolve around the following: (1) Regulatory and Signaling Networks; (2) Tumor Heterogeneity and Plasticity; and (3) Precision Oncology. PSOB members have developed and translated innovative systems biology tools with evidence of novel NY State CLIA certified tests and a broad portfolio of mechanism-based, precision oncology clinical studies, including innovative N-of-1 basket trials. The POSB Program has a strong portfolio of NCI and other cancer relevant funding. In 2019, members had a total of $10.6M in cancer-focused, peer-reviewed funding (direct costs), of which $6.8M (64%) was from NCI, $2.8M (27%) was from other NIH sources, and almost $1M (9%) was from other peer-reviewing agencies. POSB Members authored 1,064 cancer-relevant publications, of which 164 (15%) were intra-programmatic and 268 (25%) were interprogrammatic. Strikingly, 20% appeared in journals with a high impact factor (greater than 10) of which half were in journals with an impact factor of 20 or higher. The POSB Program has significant strength in leading both institutional and multicenter interventional trials. During the project period the POSB Program had 1,180 interventional enrollments of which 52% were to investigator-initiated trials. Under-represented minority and underserved patients’ accrual to interventional clinical trials is a particular strength of the POSB Program and is 29%.