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Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle.

ABSTRACT: Precision medicine aims to use patient genomic, epigenomic, specific drug dose, and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State-of-the-art techniques to measure tumor drug penetration focus on systemic exposure, tissue penetration, cellular or molecular engagement, and expression of pharmacological activity. Using in silico methods, this information can be integrated to bridge the gap between the therapeutic regimen and the pharmacological link with clinical outcome. These methodologies are described, and challenges ahead are discussed. Supported by many examples, this review shows how the combination of these techniques provides enhanced patient-specific information on drug accessibility at the tumor tissue level, target binding, and downstream pharmacology. Our vision of how to apply tumor drug penetration measurements offers a roadmap for the clinical implementation of precision dosing.

SUBMITTER: Bartelink IH

PROVIDER: S-EPMC6617978 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle.

Bartelink Imke H IH Jones Ella F EF Shahidi-Latham Sheerin K SK Lee Pei Rong Evelyn PRE Zheng Yanan Y Vicini Paolo P van 't Veer Laura L Wolf Denise D Iagaru Andrei A Kroetz Deanna L DL Prideaux Brendan B Cilliers Cornelius C Thurber Greg M GM Wimana Zena Z Gebhart Geraldine G

Clinical pharmacology and therapeutics 20181006 1

Precision medicine aims to use patient genomic, epigenomic, specific drug dose, and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State-of-the-art techniques to measure tumor drug penetration focus on systemic exposure, tissue penetration, cellular or molecular engagement, and expression of pharmacological activity. Using in silico methods, t ...[more]

PMID: 30107040

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Project description:Due to the aging of the population and despite the enormous scientific effort, Alzheimer's disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer's disease. Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer's disease led to inconclusive results, partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1, but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer's disease patients, signaling via tumor necrosis factor receptor 1. In agreement with this, choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer's disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer's disease-associated inflammation, choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in (early) Alzheimer's disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer's disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer's disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer's disease and prevent the irreversible neurodegeneration and resulting memory decline.

Dataset Information

Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle.

Publications

Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle.

Similar Datasets

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