Integrating Transcriptomic Data with Mechanistic Systems Pharmacology Models for Virtual Drug Combination Trials

Abstract

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.

In vitro modeling of the neurovascular unit: advances in the field

“…Historically dysfunctions of the BBB are associated with the onset and progression of different neurological disorders including Alzheimer's disease [26], epilepsy [27], stroke [28,29], multiple sclerosis [30], traumatic brain injury [31], amyotrophic lateral sclerosis [32] as well as schizophrenia [33]. Observed changes include alterations in BBB permeability [34,35], caused by disruption and/ or structural alteration of TJ proteins [36]. This process can be associated with the degradation of the basement membrane [37] and altered expression of efflux pumps leading to the extravasation of plasma proteins [38,39].…”

Personalized signaling models for personalized treatments

“…For instance, specific mutations in a patient can render a protein dysfunctional, and this information can be encoded in the model by removing certain nodes (proteins) or edges (interactions). Proteomic data, or transcriptomic data as a proxy, can inform on protein levels and can be used to reparametrize and personalize cell‐line‐derived models (Fey et al , ; Barrette et al , ).…”

Systems Pharmacology: Defining the Interactions of Drug Combinations

“…Parameterization of kinetic models can be challenging. Recently, it has been shown that transcriptomic profiling data derived from glioblastoma patient-derived tumor samples can be used to inform kinetic systems pharmacology models to conduct virtual drug combination trials (111). Another example described the prediction of combination therapies for B-cell lymphoma using a kinetic model of the B-cell receptor signaling network (112).…”