Dataset Information

Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine.

ABSTRACT:

Background

Hundreds of systemic chemotherapy trials in diffuse intrinsic pontine glioma (DIPG) have not improved survival, potentially due to lack of intratumoral penetration, which has not previously been assessed in humans.

Methods

We used gemcitabine as a model agent to assess DIPG intratumoral pharmacokinetics (PK) using mass spectrometry.

Results

In a phase 0 clinical trial of i.v. gemcitabine prior to biopsy in children newly diagnosed with DIPG by MRI, mean concentration in 4 biopsy cores in patient 1 (H3K27M diffuse midline glioma) was 7.65 µM. These compare favorably to levels for patient 2 (mean 3.85 µM, found to have an H3K27-wildtype low-grade glioma on histology), and from a similar study in adult glioblastoma (adjusted mean 3.48 µM). In orthotopic patient-derived xenograft (PDX) models of DIPG and H3K27M-wildtype pediatric glioblastoma, gemcitabine levels and clearance were similar in tumor, pons, and cortex and did not depend on H3K27 mutation status or tumor location. Normalized gemcitabine levels were similar in patient 1 and the DIPG PDX.

Conclusions

These findings, while limited to one agent, provide preliminary evidence for the hypotheses that lack of intratumoral penetration is not why systemic chemotherapy has failed in DIPG, and orthotopic PDX models can adequately model intratumoral PK in human DIPG.

SUBMITTER: Green AL

PROVIDER: S-EPMC7212907 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Publications

Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine.

Green Adam L AL Flannery Patrick P Hankinson Todd C TC O'Neill Brent B Amani Vladimir V DeSisto John J Knox Aaron A Chatwin Hannah H Lemma Rakeb R Hoffman Lindsey M LM Mulcahy Levy Jean J Raybin Jennifer J Hemenway Molly M Gilani Ahmed A Koschmann Carl C Dahl Nathan N Handler Michael M Pierce Angela A Venkataraman Sujatha S Foreman Nicholas N Vibhakar Rajeev R Wempe Michael F MF Dorris Kathleen K

Neuro-oncology advances 20200101 1

<h4>Background</h4>Hundreds of systemic chemotherapy trials in diffuse intrinsic pontine glioma (DIPG) have not improved survival, potentially due to lack of intratumoral penetration, which has not previously been assessed in humans.<h4>Methods</h4>We used gemcitabine as a model agent to assess DIPG intratumoral pharmacokinetics (PK) using mass spectrometry.<h4>Results</h4>In a phase 0 clinical trial of i.v. gemcitabine prior to biopsy in children newly diagnosed with DIPG by MRI, mean concentra ...[more]

PMID: 32642682

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Dataset Information

Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine.

Background

Methods

Results

Conclusions

Publications

Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine.

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