Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth

Rintaro Hashizume*, Ali Zhang, Sabine Mueller, Michael D. Prados, Rishi R. Lulla, Stewart Goldman, Amanda M. Saratsis, Andrew P. Mazar, Alexander H. Stegh, Shi Yuan Cheng, Craig Horbinski, Daphne A. Haas-Kogan, Jann N. Sarkaria, Todd Waldman, C. David James

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Background Radiation therapy is the most commonly used postsurgical treatment for primary malignant brain tumors. Consequently, investigating the efficacy of chemotherapeutics combined with radiation for treating malignant brain tumors is of high clinical relevance. In this study, we examined the cyclin-dependent kinase 4/6 inhibitor palbociclib, when used in combination with radiation for treating human atypical teratoid rhabdoid tumor (ATRT) as well as glioblastoma (GBM). Methods Evaluation of treatment antitumor activity in vitro was based upon results from cell proliferation assays, clonogenicity assays, flow cytometry, and immunocytochemistry for DNA double-strand break repair. Interpretation of treatment antitumor activity in vivo was based upon bioluminescence imaging, animal subject survival analysis, and staining of tumor sections for markers of proliferation and apoptosis. Results For each of the retinoblastoma protein (RB)-proficient tumor models examined (2 ATRTs and 2 GBMs), one or more of the combination therapy regimens significantly (P <. 05) outperformed both monotherapies with respect to animal subject survival benefit. Among the combination therapy regimens, concurrent palbociclib and radiation treatment and palbociclib treatment following radiation consistently outperformed the sequence in which radiation followed palbociclib treatment. In vitro investigation revealed that the concurrent use of palbociclib with radiation, as well as palbociclib following radiation, inhibited DNA double-strand break repair and promoted increased tumor cell apoptosis. Conclusions Our results support further investigation and possible clinical translation of palbociclib as an adjuvant to radiation therapy for patients with malignant brain tumors that retain RB expression.

Original languageEnglish (US)
Pages (from-to)1519-1528
Number of pages10
JournalNeuro-oncology
Volume18
Issue number11
DOIs
StatePublished - Nov 1 2016

Fingerprint

Glioblastoma
Heterografts
DNA Repair
DNA Damage
Radiation
Brain Neoplasms
Retinoblastoma Protein
Double-Stranded DNA Breaks
Therapeutics
Cyclin-Dependent Kinase 6
Radiotherapy
Cyclin-Dependent Kinase 4
Apoptosis
Background Radiation
palbociclib
Typical Teratoid Rhabdoid Tumor
Atypical Teratoid Tumor
Survival Analysis
Tumor Biomarkers
Neoplasms

Keywords

  • Atypical teratoid rhabdoid tumor
  • bioluminescence imaging
  • glioblastoma
  • palbociclib
  • xenograft

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

@article{085b176f4e974eeb83bc79deade87190,
title = "Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth",
abstract = "Background Radiation therapy is the most commonly used postsurgical treatment for primary malignant brain tumors. Consequently, investigating the efficacy of chemotherapeutics combined with radiation for treating malignant brain tumors is of high clinical relevance. In this study, we examined the cyclin-dependent kinase 4/6 inhibitor palbociclib, when used in combination with radiation for treating human atypical teratoid rhabdoid tumor (ATRT) as well as glioblastoma (GBM). Methods Evaluation of treatment antitumor activity in vitro was based upon results from cell proliferation assays, clonogenicity assays, flow cytometry, and immunocytochemistry for DNA double-strand break repair. Interpretation of treatment antitumor activity in vivo was based upon bioluminescence imaging, animal subject survival analysis, and staining of tumor sections for markers of proliferation and apoptosis. Results For each of the retinoblastoma protein (RB)-proficient tumor models examined (2 ATRTs and 2 GBMs), one or more of the combination therapy regimens significantly (P <. 05) outperformed both monotherapies with respect to animal subject survival benefit. Among the combination therapy regimens, concurrent palbociclib and radiation treatment and palbociclib treatment following radiation consistently outperformed the sequence in which radiation followed palbociclib treatment. In vitro investigation revealed that the concurrent use of palbociclib with radiation, as well as palbociclib following radiation, inhibited DNA double-strand break repair and promoted increased tumor cell apoptosis. Conclusions Our results support further investigation and possible clinical translation of palbociclib as an adjuvant to radiation therapy for patients with malignant brain tumors that retain RB expression.",
keywords = "Atypical teratoid rhabdoid tumor, bioluminescence imaging, glioblastoma, palbociclib, xenograft",
author = "Rintaro Hashizume and Ali Zhang and Sabine Mueller and Prados, {Michael D.} and Lulla, {Rishi R.} and Stewart Goldman and Saratsis, {Amanda M.} and Mazar, {Andrew P.} and Stegh, {Alexander H.} and Cheng, {Shi Yuan} and Craig Horbinski and Haas-Kogan, {Daphne A.} and Sarkaria, {Jann N.} and Todd Waldman and James, {C. David}",
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day = "1",
doi = "10.1093/neuonc/now106",
language = "English (US)",
volume = "18",
pages = "1519--1528",
journal = "Neuro-Oncology",
issn = "1522-8517",
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}

Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth. / Hashizume, Rintaro; Zhang, Ali; Mueller, Sabine; Prados, Michael D.; Lulla, Rishi R.; Goldman, Stewart; Saratsis, Amanda M.; Mazar, Andrew P.; Stegh, Alexander H.; Cheng, Shi Yuan; Horbinski, Craig; Haas-Kogan, Daphne A.; Sarkaria, Jann N.; Waldman, Todd; James, C. David.

In: Neuro-oncology, Vol. 18, No. 11, 01.11.2016, p. 1519-1528.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth

AU - Hashizume, Rintaro

AU - Zhang, Ali

AU - Mueller, Sabine

AU - Prados, Michael D.

AU - Lulla, Rishi R.

AU - Goldman, Stewart

AU - Saratsis, Amanda M.

AU - Mazar, Andrew P.

AU - Stegh, Alexander H.

AU - Cheng, Shi Yuan

AU - Horbinski, Craig

AU - Haas-Kogan, Daphne A.

AU - Sarkaria, Jann N.

AU - Waldman, Todd

AU - James, C. David

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Background Radiation therapy is the most commonly used postsurgical treatment for primary malignant brain tumors. Consequently, investigating the efficacy of chemotherapeutics combined with radiation for treating malignant brain tumors is of high clinical relevance. In this study, we examined the cyclin-dependent kinase 4/6 inhibitor palbociclib, when used in combination with radiation for treating human atypical teratoid rhabdoid tumor (ATRT) as well as glioblastoma (GBM). Methods Evaluation of treatment antitumor activity in vitro was based upon results from cell proliferation assays, clonogenicity assays, flow cytometry, and immunocytochemistry for DNA double-strand break repair. Interpretation of treatment antitumor activity in vivo was based upon bioluminescence imaging, animal subject survival analysis, and staining of tumor sections for markers of proliferation and apoptosis. Results For each of the retinoblastoma protein (RB)-proficient tumor models examined (2 ATRTs and 2 GBMs), one or more of the combination therapy regimens significantly (P <. 05) outperformed both monotherapies with respect to animal subject survival benefit. Among the combination therapy regimens, concurrent palbociclib and radiation treatment and palbociclib treatment following radiation consistently outperformed the sequence in which radiation followed palbociclib treatment. In vitro investigation revealed that the concurrent use of palbociclib with radiation, as well as palbociclib following radiation, inhibited DNA double-strand break repair and promoted increased tumor cell apoptosis. Conclusions Our results support further investigation and possible clinical translation of palbociclib as an adjuvant to radiation therapy for patients with malignant brain tumors that retain RB expression.

AB - Background Radiation therapy is the most commonly used postsurgical treatment for primary malignant brain tumors. Consequently, investigating the efficacy of chemotherapeutics combined with radiation for treating malignant brain tumors is of high clinical relevance. In this study, we examined the cyclin-dependent kinase 4/6 inhibitor palbociclib, when used in combination with radiation for treating human atypical teratoid rhabdoid tumor (ATRT) as well as glioblastoma (GBM). Methods Evaluation of treatment antitumor activity in vitro was based upon results from cell proliferation assays, clonogenicity assays, flow cytometry, and immunocytochemistry for DNA double-strand break repair. Interpretation of treatment antitumor activity in vivo was based upon bioluminescence imaging, animal subject survival analysis, and staining of tumor sections for markers of proliferation and apoptosis. Results For each of the retinoblastoma protein (RB)-proficient tumor models examined (2 ATRTs and 2 GBMs), one or more of the combination therapy regimens significantly (P <. 05) outperformed both monotherapies with respect to animal subject survival benefit. Among the combination therapy regimens, concurrent palbociclib and radiation treatment and palbociclib treatment following radiation consistently outperformed the sequence in which radiation followed palbociclib treatment. In vitro investigation revealed that the concurrent use of palbociclib with radiation, as well as palbociclib following radiation, inhibited DNA double-strand break repair and promoted increased tumor cell apoptosis. Conclusions Our results support further investigation and possible clinical translation of palbociclib as an adjuvant to radiation therapy for patients with malignant brain tumors that retain RB expression.

KW - Atypical teratoid rhabdoid tumor

KW - bioluminescence imaging

KW - glioblastoma

KW - palbociclib

KW - xenograft

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U2 - 10.1093/neuonc/now106

DO - 10.1093/neuonc/now106

M3 - Article

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VL - 18

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JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

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