Integrating Transcriptomic Data with Mechanistic Systems Pharmacology Models for Virtual Drug Combination Trials.
Anne Marie BarretteMehdi BouhaddouMarc R BirtwistlePublished in: ACS chemical neuroscience (2017)
Monotherapy clinical trials with mutation-targeted kinase inhibitors, despite some success in other cancers, have yet to impact glioblastoma (GBM). Besides insufficient blood-brain barrier penetration, combinations are key to overcoming obstacles such as intratumoral heterogeneity, adaptive resistance, and the epistatic nature of tumor genomics that cause mutation-targeted therapies to fail. With now hundreds of potential drugs, exploring the combination space clinically and preclinically is daunting. We are building a simulation-based approach that integrates patient-specific data with a mechanistic computational model of pan-cancer driver pathways (receptor tyrosine kinases, RAS/RAF/ERK, PI3K/AKT/mTOR, cell cycle, apoptosis, and DNA damage) to prioritize drug combinations by their simulated effects on tumor cell proliferation and death. Here we illustrate a first step, tailoring the model to 14 GBM patients from The Cancer Genome Atlas defined by an mRNA-seq transcriptome, and then simulating responses to three promiscuous FDA-approved kinase inhibitors (bosutinib, ibrutinib, and cabozantinib) with evidence for blood-brain barrier penetration. The model captures binding of the drug to primary targets and off-targets based on published affinity data and simulates responses of 100 heterogeneous tumor cells within a patient. Single drugs are marginally effective or even counterproductive. Common copy number alterations (PTEN loss, EGFR amplification, and NF1 loss) have a negligible correlation with single-drug or combination efficacy, reinforcing the importance of postgenetic approaches that account for kinase inhibitor promiscuity to match drugs to patients. Drug combinations tend to be either cytostatic or cytotoxic, but seldom both, highlighting the need for considering targeted and nontargeted therapy. Although we focus on GBM, the approach is generally applicable.
Keyphrases
- blood brain barrier
- cell proliferation
- cell cycle
- single cell
- end stage renal disease
- dna damage
- copy number
- clinical trial
- genome wide
- ejection fraction
- chronic kidney disease
- newly diagnosed
- pi k akt
- oxidative stress
- rna seq
- small cell lung cancer
- signaling pathway
- mitochondrial dna
- prognostic factors
- cerebral ischemia
- peritoneal dialysis
- electronic health record
- squamous cell carcinoma
- emergency department
- gene expression
- case report
- stem cells
- systematic review
- binding protein
- papillary thyroid
- inflammatory response
- immune response
- cancer therapy
- randomized controlled trial
- patient reported outcomes
- drug delivery
- transcription factor
- dna repair
- risk assessment
- human health
- double blind
- lps induced