Integration of genomics, high throughput drug screening, and personalized xenograft models as a novel precision medicine paradigm for high risk pediatric cancer
Pediatric high grade gliomas (HGG) are primary brain malignancies that result in significant morbidity and mortality. One of the challenges in their treatment is inter- and intra-tumoral heterogeneity. Precision medicine approaches have the potential to enhance diagnostic, prognostic and/or therapeu...
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Published in | Cancer biology & therapy Vol. 19; no. 12; pp. 1078 - 1087 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Taylor & Francis
02.12.2018
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Abstract | Pediatric high grade gliomas (HGG) are primary brain malignancies that result in significant morbidity and mortality. One of the challenges in their treatment is inter- and intra-tumoral heterogeneity. Precision medicine approaches have the potential to enhance diagnostic, prognostic and/or therapeutic information. In this case study we describe the molecular characterization of a pediatric HGG and the use of an integrated approach based on genomic, in vitro and in vivo testing to identify actionable targets and treatment options. Molecular analysis based on WGS performed on initial and recurrent tumor biopsies revealed mutations in TP53, TSC1 and CIC genes, focal amplification of MYCN, and copy number gains in SMO and c-MET. Transcriptomic analysis identified increased expression of MYCN, and genes involved in sonic hedgehog signaling proteins (SHH, SMO, GLI1, GLI2) and receptor tyrosine kinase pathways (PLK, AURKA, c-MET). HTS revealed no cytotoxic efficacy of SHH pathway inhibitors while sensitivity was observed to the mTOR inhibitor temsirolimus, the ALK inhibitor ceritinib, and the PLK1 inhibitor BI2536. Based on the integrated approach, temsirolimus, ceritinib, BI2536 and standard therapy temozolomide were selected for further in vivo evaluation. Using the PDX animal model (median survival 28 days) we showed significant in vivo activity for mTOR inhibition by temsirolimus and BI2536 (median survival 109 and 115.5 days respectively) while ceritinib and temozolomide had only a moderate effect (43 and 75.5 days median survival respectively). This case study demonstrates that an integrated approach based on genomic, in vitro and in vivo drug efficacy testing in a PDX model may be useful to guide the management of high risk pediatric brain tumor in a clinically meaningful timeframe. |
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AbstractList | Pediatric high grade gliomas (HGG) are primary brain malignancies that result in significant morbidity and mortality. One of the challenges in their treatment is inter- and intra-tumoral heterogeneity. Precision medicine approaches have the potential to enhance diagnostic, prognostic and/or therapeutic information. In this case study we describe the molecular characterization of a pediatric HGG and the use of an integrated approach based on genomic,
in vitro
and
in vivo
testing to identify actionable targets and treatment options. Molecular analysis based on WGS performed on initial and recurrent tumor biopsies revealed mutations in
TP53, TSC1
and
CIC
genes, focal amplification of
MYCN
, and copy number gains in
SMO
and
c-MET
. Transcriptomic analysis identified increased expression of
MYCN
, and genes involved in sonic hedgehog signaling proteins (
SHH, SMO, GLI1, GLI2
) and receptor tyrosine kinase pathways (
PLK, AURKA, c-MET
). HTS revealed no cytotoxic efficacy of SHH pathway inhibitors while sensitivity was observed to the mTOR inhibitor temsirolimus, the ALK inhibitor ceritinib, and the PLK1 inhibitor BI2536. Based on the integrated approach, temsirolimus, ceritinib, BI2536 and standard therapy temozolomide were selected for further
in vivo
evaluation. Using the PDX animal model (median survival 28 days) we showed significant
in vivo
activity for mTOR inhibition by temsirolimus and BI2536 (median survival 109 and 115.5 days respectively) while ceritinib and temozolomide had only a moderate effect (43 and 75.5 days median survival respectively). This case study demonstrates that an integrated approach based on genomic,
in vitro
and
in vivo
drug efficacy testing in a PDX model may be useful to guide the management of high risk pediatric brain tumor in a clinically meaningful timeframe. Pediatric high grade gliomas (HGG) are primary brain malignancies that result in significant morbidity and mortality. One of the challenges in their treatment is inter- and intra-tumoral heterogeneity. Precision medicine approaches have the potential to enhance diagnostic, prognostic and/or therapeutic information. In this case study we describe the molecular characterization of a pediatric HGG and the use of an integrated approach based on genomic, in vitro and in vivo testing to identify actionable targets and treatment options. Molecular analysis based on WGS performed on initial and recurrent tumor biopsies revealed mutations in TP53, TSC1 and CIC genes, focal amplification of MYCN, and copy number gains in SMO and c-MET. Transcriptomic analysis identified increased expression of MYCN, and genes involved in sonic hedgehog signaling proteins (SHH, SMO, GLI1, GLI2) and receptor tyrosine kinase pathways (PLK, AURKA, c-MET). HTS revealed no cytotoxic efficacy of SHH pathway inhibitors while sensitivity was observed to the mTOR inhibitor temsirolimus, the ALK inhibitor ceritinib, and the PLK1 inhibitor BI2536. Based on the integrated approach, temsirolimus, ceritinib, BI2536 and standard therapy temozolomide were selected for further in vivo evaluation. Using the PDX animal model (median survival 28 days) we showed significant in vivo activity for mTOR inhibition by temsirolimus and BI2536 (median survival 109 and 115.5 days respectively) while ceritinib and temozolomide had only a moderate effect (43 and 75.5 days median survival respectively). This case study demonstrates that an integrated approach based on genomic, in vitro and in vivo drug efficacy testing in a PDX model may be useful to guide the management of high risk pediatric brain tumor in a clinically meaningful timeframe. |
Author | Mould, Emily Cowley, Mark J Cohn, Richard J Marshall, Glenn M Haber, Michelle Liu, Jie Rodriguez, Michael Pinese, Mark Arndt, Greg Wadham, Carol Yin, Julia X Failes, Tim Franshaw, Laura Tsoli, Maria Kaplan, Warren Ekert, Paul G Joshi, Swapna Gifford, Andrew Tyrrell, Vanessa Trahair, Toby Saletta, Federica Ziegler, David S Gayevskiy, Velimir McDonald, Kerrie Weber, Martin A Kumar, Amit |
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Cancer Institute, Lowy Cancer Research Centre , University of New South Wales , Randwick , New South Wales , Australia – sequence: 6 givenname: Emily surname: Mould fullname: Mould, Emily organization: a Children's Cancer Institute, Lowy Cancer Research Centre , University of New South Wales , Randwick , New South Wales , Australia – sequence: 7 givenname: Julia X surname: Yin fullname: Yin, Julia X organization: e Cure Brain Cancer Neuro-Oncology Group , Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales , Randwick, New South Wales , Australia – sequence: 8 givenname: Velimir surname: Gayevskiy fullname: Gayevskiy, Velimir organization: f Bioinformatics and Cancer Genomics, Peter MacCallum Cancer Centre, The Sir Peter MacCallum Department of Oncology , The University of Melbourne, Melbourne , Victoria , Australia – sequence: 9 givenname: Amit surname: Kumar fullname: Kumar, Amit organization: g Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research , Parkville, Melbourne , Victoria , Australia – sequence: 10 givenname: Warren surname: Kaplan fullname: Kaplan, Warren organization: d Kinghorn Centre for Clinical Genomics , Garvan Institute of Medical Research, University of New South Wales , Randwick, New South Wales , Australia – sequence: 11 givenname: Paul G surname: Ekert fullname: Ekert, Paul G organization: h Cell Biology, Murdoch Children's Research Institute, Royal Children's Hospital , Parkville, Melbourne , Victoria , Australia – sequence: 12 givenname: Federica surname: Saletta fullname: Saletta, Federica organization: i Children's Cancer Research Unit, The Children's Hospital at Westmead , Westmead , NSW , Australia – sequence: 13 givenname: Laura surname: Franshaw fullname: Franshaw, Laura organization: a Children's Cancer Institute, Lowy Cancer Research Centre , University of New South Wales , Randwick , New South Wales , Australia – sequence: 14 givenname: Jie surname: Liu fullname: Liu, Jie organization: a Children's Cancer Institute, Lowy Cancer Research Centre , University of New South Wales , Randwick , New South Wales , Australia – sequence: 15 givenname: Andrew surname: Gifford fullname: Gifford, Andrew organization: j Anatomical Pathology, Prince of Wales Hospital , Randwick , New South Wales , Australia – sequence: 16 givenname: Martin A surname: Weber fullname: Weber, Martin A organization: j Anatomical Pathology, Prince of Wales Hospital , Randwick , New South Wales , Australia – sequence: 17 givenname: Michael surname: Rodriguez fullname: Rodriguez, Michael organization: j Anatomical Pathology, Prince of Wales Hospital , Randwick , New South Wales , Australia – sequence: 18 givenname: Richard J surname: Cohn fullname: Cohn, Richard J organization: k Kids Cancer Centre, Sydney Children's Hospital , Randwick , New South Wales , Australia – sequence: 19 givenname: Greg surname: Arndt fullname: Arndt, Greg organization: c ACRF Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute, Lowy Cancer Research Centre , University of New South Wales , Randwick , New South Wales , Australia – sequence: 20 givenname: Vanessa surname: Tyrrell fullname: Tyrrell, Vanessa organization: a Children's Cancer Institute, Lowy Cancer Research Centre , University of New South Wales , Randwick , New South Wales , Australia – sequence: 21 givenname: Michelle surname: Haber fullname: Haber, Michelle organization: a Children's Cancer Institute, Lowy Cancer Research Centre , University of New South Wales , Randwick , New South Wales , Australia – sequence: 22 givenname: Toby orcidid: 0000-0002-3295-228X surname: Trahair fullname: Trahair, Toby organization: k Kids Cancer Centre, Sydney Children's Hospital , Randwick , New South Wales , Australia – sequence: 23 givenname: Glenn M surname: Marshall fullname: Marshall, Glenn M organization: k Kids Cancer Centre, Sydney Children's Hospital , Randwick , New South Wales , Australia – sequence: 24 givenname: Kerrie surname: McDonald fullname: McDonald, Kerrie organization: e Cure Brain Cancer Neuro-Oncology Group , Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales , Randwick, New South Wales , Australia – sequence: 25 givenname: Mark J surname: Cowley fullname: Cowley, Mark J organization: l St Vincent's Clinical School , University of New South Wales , Randwick , New South Wales , Australia – sequence: 26 givenname: David S surname: Ziegler fullname: Ziegler, David S organization: k Kids Cancer Centre, Sydney Children's Hospital , Randwick , New South Wales , Australia |
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Keywords | patient derived xenografts pediatric brain tumors high throughput drug screening personalized medicine targeted treatment |
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Notes | ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3 Maria Tsoli, Carol Wadham, Mark Pinese, Kerrie McDonald, Mark J. Cowley and David S. Ziegler contributed equally to the manuscript.Supplemental data for this article can be accessed here. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kcbt. |
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Title | Integration of genomics, high throughput drug screening, and personalized xenograft models as a novel precision medicine paradigm for high risk pediatric cancer |
URI | https://www.ncbi.nlm.nih.gov/pubmed/30299205 https://search.proquest.com/docview/2117393050 https://pubmed.ncbi.nlm.nih.gov/PMC6301829 https://doaj.org/article/40d80c282f0c4c19a65cd0dbc3b32bea |
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