Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma

Randall, Elizabeth C.; Emdal, Kristina B.; Laramy, Janice K.; Kim, Minjee; Roos, Alison; Calligaris, David; Regan, Michael S.; Gupta, Shiv K.; Mladek, Ann C.; Carlson, Brett L.; Johnson, Aaron J.; Lu, Fa Ke; Xie, X. Sunney; Joughin, Brian A.; Reddy, Raven J.; Peng, Sen; Abdelmoula, Walid M.; Jackson, Pamela; Kolluri, Aarti; Kellersberger, Katherine A.; Agar, Jeffrey N.; Lauffenburger, Douglas A.; Swanson, Kristin R.; Tran, Nhan L.; Elmquist, William F.; White, Forest M.; Sarkaria, Jann N.; Agar, Nathalie Y.R.

doi:10.1038/s41467-018-07334-3

Cited by 66 publications

(47 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Differential responsiveness of brain and non-brain PDXs to anti-cancer drugs has been observed in at least one other study [53]. There are several mechanisms to explain the difference between orthotopic and ectopic PDXs in response to epothilone B.…”

Section: Discussionmentioning

confidence: 78%

Novel Breast Cancer Brain Metastasis Patient-Derived Orthotopic Xenograft Model for Preclinical Studies

Oshi

Okano

Maiti

et al. 2020

Cancers

View full text Add to dashboard Cite

The vast majority of mortality in breast cancer results from distant metastasis. Brain metastases occur in as many as 30% of patients with advanced breast cancer, and the 1-year survival rate of these patients is around 20%. Pre-clinical animal models that reliably reflect the biology of breast cancer brain metastasis are needed to develop and test new treatments for this deadly condition. The patient-derived xenograft (PDX) model maintains many features of a donor tumor, such as intra-tumor heterogeneity, and permits the testing of individualized treatments. However, the establishment of orthotopic PDXs of brain metastasis is procedurally difficult. We have developed a method for generating such PDXs with high tumor engraftment and growth rates. Here, we describe this method and identify variables that affect its outcomes. We also compare the brain-orthotopic PDXs with ectopic PDXs grown in mammary pads of mice, and show that the responsiveness of PDXs to chemotherapeutic reagents can be dramatically affected by the site that they are in.

show abstract

Section: Discussionmentioning

confidence: 78%

Novel Breast Cancer Brain Metastasis Patient-Derived Orthotopic Xenograft Model for Preclinical Studies

Oshi

Okano

Maiti

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…This is supported by diverse murine studies showing a low drug penetration into tumors of xenografted mice [331][332][333] and PDGF-B-driven brainstem glioma models [334], due to ABC transporters P-gp and Bcrp [333,334]. In addition, a recent study using 3D-MSI showed a higher but non-homogeneous accumulation of erlotinib in the GBM tumors of xenografted mice than in brain parenchyma, proving that the BBTB is heterogeneously disrupted across the tumor [335].…”

Section: Multidrug Resistance In Glioma and The Blood-brain Tumor Barmentioning

confidence: 76%

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

et al. 2019

View full text Add to dashboard Cite

Drug delivery into the brain is regulated by the blood–brain interfaces. The blood–brain barrier (BBB), the blood–cerebrospinal fluid barrier (BCSFB), and the blood–arachnoid barrier (BAB) regulate the exchange of substances between the blood and brain parenchyma. These selective barriers present a high impermeability to most substances, with the selective transport of nutrients and transporters preventing the entry and accumulation of possibly toxic molecules, comprising many therapeutic drugs. Transporters of the ATP-binding cassette (ABC) superfamily have an important role in drug delivery, because they extrude a broad molecular diversity of xenobiotics, including several anticancer drugs, preventing their entry into the brain. Gliomas are the most common primary tumors diagnosed in adults, which are often characterized by a poor prognosis, notably in the case of high-grade gliomas. Therapeutic treatments frequently fail due to the difficulty of delivering drugs through the brain barriers, adding to diverse mechanisms developed by the cancer, including the overexpression or expression de novo of ABC transporters in tumoral cells and/or in the endothelial cells forming the blood–brain tumor barrier (BBTB). Many models have been developed to study the phenotype, molecular characteristics, and function of the blood–brain interfaces as well as to evaluate drug permeability into the brain. These include in vitro, in vivo, and in silico models, which together can help us to better understand their implication in drug resistance and to develop new therapeutics or delivery strategies to improve the treatment of pathologies of the central nervous system (CNS). In this review, we present the principal characteristics of the blood–brain interfaces; then, we focus on the ABC transporters present on them and their implication in drug delivery; next, we present some of the most important models used for the study of drug transport; finally, we summarize the implication of ABC transporters in glioma and the BBTB in drug resistance and the strategies to improve the delivery of CNS anticancer drugs.

show abstract

“…Most models used in drug R&D programs are not spatially resolved, despite there being clear evidence that the spatial structure of tumors will considerably affect tumor response to treatment. 85,86 This contrasts with the academic literature on tumor modeling where spatially resolved models have been developed. 87 Spatial effects of clear relevance to predicting patient response include potential structural and genetic heterogeneity within tumors.…”

Section: Mathematical Modeling Approaches To Translation In Oncologymentioning

confidence: 97%

“…87 Spatial effects of clear relevance to predicting patient response include potential structural and genetic heterogeneity within tumors. Considering drug concentration gradients in tumors, stromal architecture can affect drug availability by several orders of magnitude 85 and can drive drug-resistant clonal selection. 88 Modeling approaches could encompass detailed tumor simulations of drug availability 89 through to classification-based approaches where architecture can be used to predict responsiveness.…”

Section: Mathematical Modeling Approaches To Translation In Oncologymentioning

confidence: 99%

Opportunities for Quantitative Translational Modeling in Oncology

Yates

Byrne

Chapman

et al. 2020

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

A 2‐day meeting was held by members of the UK Quantitative Systems Pharmacology Network () in November 2018 on the topic of Translational Challenges in Oncology. Participants from a wide range of backgrounds were invited to discuss current and emerging modeling applications in nonclinical and clinical drug development, and to identify areas for improvement. This resulting perspective explores opportunities for impactful quantitative pharmacology approaches. Four key themes arose from the presentations and discussions that were held, leading to the following recommendations: Evaluate the predictivity and reproducibility of animal cancer models through precompetitive collaboration. Apply mechanism of action (MoA) based mechanistic models derived from nonclinical data to clinical trial data. Apply MoA reflective models across trial data sets to more robustly quantify the natural history of disease and response to differing interventions. Quantify more robustly the dose and concentration dependence of adverse events through mathematical modelling techniques and modified trial design.

show abstract

Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma

Cited by 66 publications

References 44 publications

Novel Breast Cancer Brain Metastasis Patient-Derived Orthotopic Xenograft Model for Preclinical Studies

Novel Breast Cancer Brain Metastasis Patient-Derived Orthotopic Xenograft Model for Preclinical Studies

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

Opportunities for Quantitative Translational Modeling in Oncology

Contact Info

Product

Resources

About