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

Published on Aug 21, 2020in Frontiers in Physiology4.566
· DOI :10.3389/FPHYS.2020.00830
Susan Christine Massey7
Estimated H-index: 7
(Mayo Clinic),
Javier Urcuyo1
Estimated H-index: 1
(Mayo Clinic)
+ 2 AuthorsKristin R. Swanson48
Estimated H-index: 48
(ASU: Arizona State University)
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.
#1Susan Christine Massey (Mayo Clinic)H-Index: 7
#2Javier UrcuyoH-Index: 1
Last. Kristin R. Swanson (ASU: Arizona State University)H-Index: 48
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Many drugs investigated for the treatment of glioblastoma (GBM) have had poor clinical outcomes, as their efficacy is dependent on adequate delivery to sensitive tumor cell populations, which is limited by the blood-brain barrier (BBB). Further complicating evaluation of therapeutic efficacy, tumors can become resistant to anti-cancer drugs, and it can be difficult to gauge the extent to which BBB limitations and resistance each contribute to a drug9s failure. To address this question, we develo...
#1Bianca M Marin (Mayo Clinic)H-Index: 2
#2Ann C. Mladek (Mayo Clinic)H-Index: 21
Last. Jann N. Sarkaria (Mayo Clinic)H-Index: 70
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#1Eskil Eskilsson (University of Texas MD Anderson Cancer Center)H-Index: 10
#2Gro V. Røsland (University of Bergen)H-Index: 16
Last. Hrvoje Miletic (University of Bergen)H-Index: 36
view all 10 authors...
: Patients with glioblastoma (GBM) have a universally poor prognosis and are in urgent need of effective treatment strategies. Recent advances in sequencing techniques unraveled the complete genomic landscape of GBMs and revealed profound heterogeneity of individual tumors even at the single cell level. Genomic profiling has detected epidermal growth factor receptor (EGFR) gene alterations in more than half of GBMs. Major genetic events include amplification and mutation of EGFR. Yet, treatment ...
#1Shayna Stein (Broad Institute)H-Index: 5
#2Rui Zhao (Harvard University)H-Index: 50
Last. Franziska Michor (Broad Institute)H-Index: 72
view all 5 authors...
Human primary glioblastomas (GBM) often harbor mutations within the epidermal growth factor receptor (EGFR). Treatment of EGFR-mutant GBM cell lines with the EGFR/HER2 tyrosine kinase inhibitor lapatinib can effectively induce cell death in these models. However, EGFR inhibitors have shown little efficacy in the clinic, partly because of inappropriate dosing. Here, we developed a computational approach to model the in vitro cellular dynamics of the EGFR-mutant cell line SF268 in response to diff...
#1Martin J. van den Bent (EUR: Erasmus University Rotterdam)H-Index: 101
#2Hui K Gan (University of Melbourne)H-Index: 35
Last. David A. Reardon (Harvard University)H-Index: 110
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Purpose Patients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~ 50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody–drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monotherapy at ...
#1David A. Reardon (Harvard University)H-Index: 110
#2Andrew B. Lassman (Columbia University)H-Index: 16
Last. Hui K Gan (University of Melbourne)H-Index: 35
view all 18 authors...
Background: The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR). Methods: In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intra...
#1O. van Tellingen (NKI-AVL: Netherlands Cancer Institute)H-Index: 33
#2B. Yetkin-Arik (VUmc: VU University Medical Center)H-Index: 1
Last. H. de Vries (VUmc: VU University Medical Center)H-Index: 24
view all 6 authors...
Abstract Gliomas are the most common primary brain tumors. Particularly in adult patients, the vast majority of gliomas belongs to the heterogeneous group of diffuse gliomas, i.e . glial tumors characterized by diffuse infiltrative growth in the preexistent brain tissue. Unfortunately, glioblastoma, the most aggressive (WHO grade IV) diffuse glioma is also by far the most frequent one. After standard treatment, the 2-year overall survival of glioblastoma patients is approximately only 25%. Advan...
#1Chibawanye I. Ene (UW: University of Washington)H-Index: 13
#2Eric C. Holland (UW: University of Washington)H-Index: 95
Personalized medicine for cancer entails tailoring therapy for each patient based on unique features of the patient's tumor; physiologic, molecular, genetic and epigenetic. Our ability to molecularly characterize tumor cells has increased dramatically and shown that there are significant differences between samples from patients with the same tumor type. Given this extensive variability in mutations and pathways driving tumors in patients, seeking a single bullet is an unrealistic approach for a...
#5Guillemette Chapuisat (AMU: Aix-Marseille University)H-Index: 12
Defining tumor stage at diagnosis is a pivotal point for clinical decisions about patient treatment strategies. In this respect, early detection of occult metastasis invisible to current imaging methods would have a major impact on best care and long-term survival. Mathematical models that describe metastatic spreading might estimate the risk of metastasis when no clinical evidence is available. In this study, we adapted a top-down model to make such estimates. The model was constituted by a tra...
#1Anne Baldock (NU: Northwestern University)H-Index: 5
#2Sunyoung Ahn (UW: University of Washington)H-Index: 4
Last. Kristin R. Swanson (NU: Northwestern University)H-Index: 48
view all 22 authors...
Object Malignant gliomas are incurable, primary brain neoplasms noted for their potential to extensively invade brain parenchyma. Current methods of clinical imaging do not elucidate the full extent of brain invasion, making it difficult to predict which, if any, patients are likely to benefit from gross total resection. Our goal was to apply a mathematical modeling approach to estimate the overall tumor invasiveness on a patient-by-patient basis and determine whether gross total resection would...
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