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Quantifying Glioblastoma Drug Response Dynamics Incorporating Treatment Sensitivity and Blood Brain Barrier
Susan Christine Massey1, Javier C Urcuyo1, Bianca Maria Marin2
1Precision Neurotherapeutics Innovation Program, Mayo Clinic, Phoenix, AZ, United States.
Abstract:
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.
Insights
A new mathematical model suggests the blood-brain barrier (BBB) significantly impacts glioblastoma (GBM) drug efficacy. BBB permeability appears more critical than tumor cell drug sensitivity for treatment success.
Area of Science:
- Pharmacology
- Mathematical Biology
- Oncology
Background:
- Glioblastoma (GBM) treatment faces challenges due to poor drug delivery across the blood-brain barrier (BBB) and inherent tumor cell heterogeneity.
- These factors limit the efficacy of many investigational anti-cancer drugs, leading to disappointing clinical trial outcomes.
Purpose of the Study:
- To develop a mathematical model to dissect the contributions of BBB limitations and tumor cell drug sensitivity to overall therapeutic response in glioblastoma.
- To quantify the relative impact of BBB permeability versus heterogeneous drug sensitivity on treatment outcomes.
Main Methods:
- A minimal mathematical model was created and fitted to time-series bioluminescence imaging data from patient-derived xenograft (PDX) models of glioblastoma.
- Nonlinear regression was used to estimate model parameters, followed by simulations and sensitivity analysis using Latin hypercube sampling and partial rank correlation coefficients.
Main Results:
- Model simulations and sensitivity analysis indicated that blood-brain barrier permeability plays a more significant role in therapeutic efficacy compared to relative drug sensitivity.
- Parameter estimation provided insights into the dynamics of drug response in the experimental model.
Conclusions:
- The blood-brain barrier presents a substantial hurdle for glioblastoma drug efficacy, potentially more so than tumor cell-intrinsic resistance.
- Mathematical modeling offers a valuable approach to understand and potentially overcome therapeutic limitations in glioblastoma treatment.
- Recommendations for future experimental designs are proposed based on model insights to improve drug development for glioblastoma.
