Journal: bioRxiv
Article Title: The OncoLoop Network-based Precision Cancer Medicine Framework
doi: 10.1101/2022.02.11.479456
Figure Lengend Snippet: A. Conceptual overview : OncoLoop was designed to identify high-fidelity (cognate) models of a patient tumor— i.e. , GEMM-derived tumors (GEMM-DTs), in this study—as well as drugs capable of inverting the activity of MR proteins identified from both the patient and his cognate GEMM-DT samples for follow-up, patient-relevant validation. To accomplish this goal, OncoLoop performs integrative analysis of transcriptomic (RNA-seq) profiles from a patient tumor, his cognate model, and large-scale drug perturbation assays. B. Regulatory network analysis : Gene expression profiles generated from each data source were used to reverse-engineer species- and cohort-specific regulatory networks, which are then used to transform differential gene expression signature from individual samples into differential protein activity profiles. Drug perturbation profiles were analyzed with patient-derived networks (See Methods). C. OncoLoop analysis : Gene Set Enrichment Analysis, as implemented by the aREA algorithm , was used to assess the overlap in differentially active MR proteins between a human tumor and its cognate GEMM-DTs ( OncoMatch algorithm ). Similarly, aREA-based enrichment analysis was used to identify drugs capable of inverting the activity of a tumor’s MRs in drug- vs. vehicle control treated cells ( MR-inverter drugs ), for each patient and cognate GEMM-DT(s) pairs. D. Drug prediction and validation: Representative Circos plot illustrating PGD-loops generated by matching a patient (P) to a GEMM-DT (G) by identifying the same MR-inverter drug (D) for both. Candidate drugs were first prioritized by pharmacotype analysis (i.e., subset of patients/GEMM-DTs predicted to be sensitive to the same subset of drugs) and then validated in vivo using, both in cognate GEMM-DT-derived allografts as well as in MR-matched PDX models.
Article Snippet: Cell Line RNA-seq profiles were downloaded from the Broad Institute web portal ( https://data.broadinstitute.org/ccle/ ) from the Cancer Cell Line Encyclopedia (CCLE) as transcript per million (TPM) measurements with timestamp version 20180929.
Techniques: Derivative Assay, Activity Assay, Biomarker Discovery, RNA Sequencing, Gene Expression, Generated, Control, In Vivo