Optimization of the time course of stromal modulation and minimization of drug-drug interactions in a multiple tyrosine kinase inhibitor/gemcitabine combination in pancreatic cancer
Trueman, Sheryl A.
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Pancreatic cancer (PaCA) is the fourth leading cause of cancer related deaths, with marginal responses to monotherapy. Combinations of tyrosine kinase inhibitors with gemcitabine have been explored to enhance patient outcomes, but minimal benefits have been produced in the clinic. Nominal therapeutic responses can be explained by sub-optimal dosing regimens that may neglect drug-drug interactions, or time-dependent effects on drug delivery, metastasis, and chemosensitization. Inadequate drug delivery is one of the major factors leading to the failure of chemotherapy in pancreatic cancer (PaCA). Stromal amplification and sparse, malformed vasculature hinder tumor drug delivery and intra-tumor distribution of chemotherapeutic agents. Dovitinib (TKI-258) was used as a representative targeted agent that could potentially act as a stromal modifier in combination with gemcitabine, and we investigated the time-dependent and transient effects of these combined drugs on stromal components and drug delivery. Key signaling pathways involved in stromal amplification and neovascularization are targeted by dovitinib, through inhibition of fibroblast growth factor (FGF), vascular endothelial growth factor receptor (VEGF) and platelet derived growth factor (PDGF) receptors. Targeting multiple aberrant signaling pathways could potentially impact a broader range of processes involved in stromal amplification and angiogenesis and may overcome compensatory forms of resistance. The ability of TKIs to target such an array of pathways is derived from their mechanism of action, which was designed to bind to the ATP regulatory pockets of growth factor receptors and compete at the ATP binding site. Broad selectivity may enhance stromal modulation of dovitinib, but its promiscuity can result in off-target effects. In vivo, dosing regimens of 10-14 days demonstrably altered stromal structure, and increased tumor permeability and deposition of probes as large as 80 nm liposomes. Our investigations also demonstrated that dovitinib concurrent with gemcitabine inhibits tumor uptake of gemcitabine, most likely via the equilibrative nucleoside transporter (ENT) that is the primary mechanism of its cellular uptake. This double edge sword requires simultaneous optimization of time-dependent stromal modulation in combination with mediation of ENT transporter interactions in a dosing regimen. The impact of scheduling on drug response was investigated both in vitro and in vivo models of PaCA. Cell lines and patient-derived xenograft models were selected for their recapitulation of genomic mutations and morphological characteristics of PaCA. Our results demonstrated that the effects of stromal modulation is transient and requires precise scheduling to optimize drug delivery. Additionally, increased gemcitabine deposition and efficacy was observed until drug-drug interactions avoided, which required a 48 hour dovitinib washout period in vivo. Results indicate that by avoiding concomitant drug exposure, more f enhanced pharmacodynamic responses can be produced. These results suggest that failures of the dosing regimen that integrate novel agents into standard-of-care may fail owing to failure to understand and mitigate drug interactions, rather than poor efficacy of the combination.