The Costello lab is a computational systems biology lab that pairs wet and dry research. We combine genome-scale data, functional genomics and mechanistic experiments to understand how cancers develop and how they escape therapy. Our work is organized around three areas.

1. Chemotherapy resistance mechanisms
Resistance to platinum-based chemotherapy limits survival across many solid tumors. Using whole-genome CRISPR screens in cisplatin-resistant bladder cancer cells, we identified NPEPPS as a druggable driver of cisplatin resistance. NPEPPS binds the volume-regulated anion channel (VRAC) subunits LRRC8A and LRRC8D and limits cisplatin import into the cell. The NPEPPS to VRAC expression ratio predicts cisplatin response across patient cohorts. We are now defining how NPEPPS works at the molecular level and testing whether blocking it makes bladder and ovarian cancers more sensitive to both chemotherapy and immunotherapy.

2. Molecular mechanisms of cancer development
We identify the genomic and signaling events that drive tumor initiation, progression and metastasis. In prostate cancer, we study how co-occurring alterations such as MAP3K7 and CHD1 loss shape androgen receptor signaling and aggressive disease. In bladder cancer, we are evaluating the impact of innervation near the tumor-stroma boundary on tumor development, progression, and response to treatment.

3. Computational methods to disentangle molecular processes and pathways
Molecular datasets often blend many overlapping signals from different cell types, pathways and co-occurring conditions. We develop computational methods that separate these signals into interpretable biology. Examples include GRACKLE, a matrix factorization approach for multi-omic data, and pathway-level models of co-occurring conditions in Down syndrome. Newer directions include knowledge graph inference and AI-driven tools for generating hypotheses.

Leadership and Training

Co-Director, Biostatistics and Bioinformatics Shared Resource (BBSR). The BBSR is a shared resource of the University of Colorado Anschutz Cancer Center. It provides biostatistical and bioinformatic expertise at every stage of cancer research, from study design and sample size planning for grants and clinical trials through data analysis and manuscript preparation. Its bioinformatics group analyzes original and public omics data, builds interactive analysis platforms that investigators use to explore their own datasets, and offers training and a seminar series that link wet lab research with modern analytic methods. See the home page for more details.

Co-Director, Pharmacology and Molecular Medicine (PharMM) PhD Training Program. PharMM is an interdisciplinary, interdepartmental PhD program that trains students to study the molecular mechanisms of disease and find new paths to therapy. It one of the longest-standing pharmacology training programs in the country. Dr. Costello is Principal Investigator of the current award (2025 to 2030). See the home page for more details.