Quantifying Glioblastoma Drug Response Dynamics Incorporating Treatment Sensitivity and Blood Brain Barrier Penetrance From Experimental Data.


:Many drugs investigated for the treatment of glioblastoma (GBM) have had disappointing clinical trial results. Efficacy of these agents is dependent on adequate delivery to sensitive tumor cell populations, which is limited by the blood-brain barrier (BBB). Additionally, tumor heterogeneity can lead to subpopulations of cells with different sensitivities to anti-cancer drugs, further impacting therapeutic efficacy. Thus, it may be important to evaluate the extent to which BBB limitations and heterogeneous sensitivity each contribute to a drug's failure. To address this challenge, we developed a minimal mathematical model to characterize these elements of overall drug response, informed by time-series bioluminescence imaging data from a treated patient-derived xenograft (PDX) experimental model. By fitting this mathematical model to a preliminary dataset in a series of nonlinear regression steps, we estimated parameter values for individual PDX subjects that correspond to the dynamics seen in experimental data. Using these estimates as a guide for parameter ranges, we ran model simulations and performed a parameter sensitivity analysis using Latin hypercube sampling and partial rank correlation coefficients. Results from this analysis combined with simulations suggest that BBB permeability may play a slightly greater role in therapeutic efficacy than relative drug sensitivity. Additionally, we discuss recommendations for future experiments based on insights gained from this model. Further research in this area will be vital for improving the development of effective new therapies for glioblastoma patients.


Front Physiol


Frontiers in physiology


Massey SC,Urcuyo JC,Marin BM,Sarkaria JN,Swanson KR




Has Abstract


2020-08-21 00:00:00








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    pub_type: 杂志文章


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    authors: Bosy-Westphal A,Braun W,Schautz B,Müller MJ

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    authors: Treff G,Winkert K,Sareban M,Steinacker JM,Becker M,Sperlich B

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    pub_type: 杂志文章


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