Establishing a preclinical multidisciplinary board for brain tumors

Birgit V. Nimmervoll, Nidal Boulos, Brandon Bianski, Jason Dapper, Michael Decuypere, Anang Shelat, Sabrina Terranova, Hope E. Terhune, Amar Gajjar, Yogesh T. Patel, Burgess B. Freeman, Arzu Onar-Thomas, Clinton F. Stewart, Martine F. Roussel, R. Kipling Guy, Thomas E. Merchant, Christopher Calabrese, Karen D. Wright, Richard J. Gilbertson

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials. Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with "standard-of-care" surgery and radiotherapy. Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP. Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC.

Original languageEnglish (US)
Pages (from-to)1654-1666
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number7
DOIs
StatePublished - Apr 1 2018

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Brain Neoplasms
gemcitabine
Ependymoma
Therapeutics
Radiotherapy
Drug Repositioning
Drug Therapy
Triage
Neurosurgery
Standard of Care
Neoplasms
Research Design
Pharmacokinetics
Clinical Trials
Choroid Plexus Carcinoma

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Nimmervoll, B. V., Boulos, N., Bianski, B., Dapper, J., Decuypere, M., Shelat, A., ... Gilbertson, R. J. (2018). Establishing a preclinical multidisciplinary board for brain tumors. Clinical Cancer Research, 24(7), 1654-1666. https://doi.org/10.1158/1078-0432.CCR-17-2168

Establishing a preclinical multidisciplinary board for brain tumors. / Nimmervoll, Birgit V.; Boulos, Nidal; Bianski, Brandon; Dapper, Jason; Decuypere, Michael; Shelat, Anang; Terranova, Sabrina; Terhune, Hope E.; Gajjar, Amar; Patel, Yogesh T.; Freeman, Burgess B.; Onar-Thomas, Arzu; Stewart, Clinton F.; Roussel, Martine F.; Kipling Guy, R.; Merchant, Thomas E.; Calabrese, Christopher; Wright, Karen D.; Gilbertson, Richard J.

In: Clinical Cancer Research, Vol. 24, No. 7, 01.04.2018, p. 1654-1666.

Research output: Contribution to journalArticle

Nimmervoll, BV, Boulos, N, Bianski, B, Dapper, J, Decuypere, M, Shelat, A, Terranova, S, Terhune, HE, Gajjar, A, Patel, YT, Freeman, BB, Onar-Thomas, A, Stewart, CF, Roussel, MF, Kipling Guy, R, Merchant, TE, Calabrese, C, Wright, KD & Gilbertson, RJ 2018, 'Establishing a preclinical multidisciplinary board for brain tumors', Clinical Cancer Research, vol. 24, no. 7, pp. 1654-1666. https://doi.org/10.1158/1078-0432.CCR-17-2168
Nimmervoll, Birgit V. ; Boulos, Nidal ; Bianski, Brandon ; Dapper, Jason ; Decuypere, Michael ; Shelat, Anang ; Terranova, Sabrina ; Terhune, Hope E. ; Gajjar, Amar ; Patel, Yogesh T. ; Freeman, Burgess B. ; Onar-Thomas, Arzu ; Stewart, Clinton F. ; Roussel, Martine F. ; Kipling Guy, R. ; Merchant, Thomas E. ; Calabrese, Christopher ; Wright, Karen D. ; Gilbertson, Richard J. / Establishing a preclinical multidisciplinary board for brain tumors. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 7. pp. 1654-1666.
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AU - Nimmervoll, Birgit V.

AU - Boulos, Nidal

AU - Bianski, Brandon

AU - Dapper, Jason

AU - Decuypere, Michael

AU - Shelat, Anang

AU - Terranova, Sabrina

AU - Terhune, Hope E.

AU - Gajjar, Amar

AU - Patel, Yogesh T.

AU - Freeman, Burgess B.

AU - Onar-Thomas, Arzu

AU - Stewart, Clinton F.

AU - Roussel, Martine F.

AU - Kipling Guy, R.

AU - Merchant, Thomas E.

AU - Calabrese, Christopher

AU - Wright, Karen D.

AU - Gilbertson, Richard J.

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N2 - Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials. Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with "standard-of-care" surgery and radiotherapy. Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP. Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC.

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