Cargando…

EPEN-08. COMBINED PDGFR INHIBITOR AXITINIB AND RETINOID TRETINOIN DECREASES PROLIFERATION AND HIGH-RISK NEOPLASTIC SUBPOPULATION PROPORTIONS PFA EPENDYMOMA

Ependymoma (EPN) is fatal in over 50% of children and has not seen any therapeutic improvements in over 30 years. Based on data from single-cell RNA sequencing (scRNAseq) and large-scale screening of FDA-approved oncology compounds in posterior fossa group A (PFA) EPN, we hypothesized that combinati...

Descripción completa

Detalles Bibliográficos
Autores principales: Donson, Andrew, Grimaldo, Enrique, Riemondy, Kent, Griesinger, Andrea, Amani, Vladimir, Brunt, Breauna, Pierce, Angela, Foreman, Nicholas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260112/
http://dx.doi.org/10.1093/neuonc/noad073.112
_version_ 1785057791537315840
author Donson, Andrew
Grimaldo, Enrique
Riemondy, Kent
Griesinger, Andrea
Amani, Vladimir
Brunt, Breauna
Pierce, Angela
Foreman, Nicholas
author_facet Donson, Andrew
Grimaldo, Enrique
Riemondy, Kent
Griesinger, Andrea
Amani, Vladimir
Brunt, Breauna
Pierce, Angela
Foreman, Nicholas
author_sort Donson, Andrew
collection PubMed
description Ependymoma (EPN) is fatal in over 50% of children and has not seen any therapeutic improvements in over 30 years. Based on data from single-cell RNA sequencing (scRNAseq) and large-scale screening of FDA-approved oncology compounds in posterior fossa group A (PFA) EPN, we hypothesized that combination of PDGFR inhibitors and retinoids therapy will selectively deplete aggressive mesenchymal and undifferentiated EPN subpopulations resulting in therapeutic benefit. In vitro screening of a panel of three receptor PDGFR inhibitors (PDGFRIs) and nine retinoid analogues in high-risk chromosome 1q+/6q- PFA cell lines MAF-811 and MAF-928 was performed to identify those drugs with (i) anti-proliferative effect (tritiated thymidine incorporation and live-cell imaging), (ii) depletion of high-risk associated neoplastic subpopulations (qRT-PCR using subpopulation specific markers and scRNAseq), and (iii) synergistic effects. PDGFRIs axitinib and pazopanib and retinoids tazarotene, adapalene and tretinoin showed superior potency versus other analogues. qRT-PCR showed that tazarotene and axitinib demonstrated beneficial subpopulation perturbation. Combination of the top two PDGFRIs (axitinib and pazopanib) and retinoids (tazarotene and tretinoin) demonstrated that axitinib combined with tretinoin provided the strongest synergistic anti-proliferative effect and depletion of high-risk-associated undifferentiated subpopulations. More definitive scRNAseq subpopulation analysis revealed a reduction of mesenchymal cells in MAF-811 in response to combined axitinib/tretinoin treatments. In both MAF-811 and MAF-928 there was a net increase in the proportion of differentiated subpopulations, which are associated with a more favorable clinical outcome, in response to combined axitinib/tretinoin, collectively supporting our original hypothesis. These results demonstrate that combined RTKi axitinib and retinoid tretinoin treatment has a synergistic anti-proliferative effect and reduction of high-risk subpopulation proportions. The effect of combined axitinib and tretinoin on survival and subpopulation perturbation is now being explored in vivo.
format Online
Article
Text
id pubmed-10260112
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-102601122023-06-13 EPEN-08. COMBINED PDGFR INHIBITOR AXITINIB AND RETINOID TRETINOIN DECREASES PROLIFERATION AND HIGH-RISK NEOPLASTIC SUBPOPULATION PROPORTIONS PFA EPENDYMOMA Donson, Andrew Grimaldo, Enrique Riemondy, Kent Griesinger, Andrea Amani, Vladimir Brunt, Breauna Pierce, Angela Foreman, Nicholas Neuro Oncol Final Category: Ependymoma - EPEN Ependymoma (EPN) is fatal in over 50% of children and has not seen any therapeutic improvements in over 30 years. Based on data from single-cell RNA sequencing (scRNAseq) and large-scale screening of FDA-approved oncology compounds in posterior fossa group A (PFA) EPN, we hypothesized that combination of PDGFR inhibitors and retinoids therapy will selectively deplete aggressive mesenchymal and undifferentiated EPN subpopulations resulting in therapeutic benefit. In vitro screening of a panel of three receptor PDGFR inhibitors (PDGFRIs) and nine retinoid analogues in high-risk chromosome 1q+/6q- PFA cell lines MAF-811 and MAF-928 was performed to identify those drugs with (i) anti-proliferative effect (tritiated thymidine incorporation and live-cell imaging), (ii) depletion of high-risk associated neoplastic subpopulations (qRT-PCR using subpopulation specific markers and scRNAseq), and (iii) synergistic effects. PDGFRIs axitinib and pazopanib and retinoids tazarotene, adapalene and tretinoin showed superior potency versus other analogues. qRT-PCR showed that tazarotene and axitinib demonstrated beneficial subpopulation perturbation. Combination of the top two PDGFRIs (axitinib and pazopanib) and retinoids (tazarotene and tretinoin) demonstrated that axitinib combined with tretinoin provided the strongest synergistic anti-proliferative effect and depletion of high-risk-associated undifferentiated subpopulations. More definitive scRNAseq subpopulation analysis revealed a reduction of mesenchymal cells in MAF-811 in response to combined axitinib/tretinoin treatments. In both MAF-811 and MAF-928 there was a net increase in the proportion of differentiated subpopulations, which are associated with a more favorable clinical outcome, in response to combined axitinib/tretinoin, collectively supporting our original hypothesis. These results demonstrate that combined RTKi axitinib and retinoid tretinoin treatment has a synergistic anti-proliferative effect and reduction of high-risk subpopulation proportions. The effect of combined axitinib and tretinoin on survival and subpopulation perturbation is now being explored in vivo. Oxford University Press 2023-06-12 /pmc/articles/PMC10260112/ http://dx.doi.org/10.1093/neuonc/noad073.112 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Final Category: Ependymoma - EPEN
Donson, Andrew
Grimaldo, Enrique
Riemondy, Kent
Griesinger, Andrea
Amani, Vladimir
Brunt, Breauna
Pierce, Angela
Foreman, Nicholas
EPEN-08. COMBINED PDGFR INHIBITOR AXITINIB AND RETINOID TRETINOIN DECREASES PROLIFERATION AND HIGH-RISK NEOPLASTIC SUBPOPULATION PROPORTIONS PFA EPENDYMOMA
title EPEN-08. COMBINED PDGFR INHIBITOR AXITINIB AND RETINOID TRETINOIN DECREASES PROLIFERATION AND HIGH-RISK NEOPLASTIC SUBPOPULATION PROPORTIONS PFA EPENDYMOMA
title_full EPEN-08. COMBINED PDGFR INHIBITOR AXITINIB AND RETINOID TRETINOIN DECREASES PROLIFERATION AND HIGH-RISK NEOPLASTIC SUBPOPULATION PROPORTIONS PFA EPENDYMOMA
title_fullStr EPEN-08. COMBINED PDGFR INHIBITOR AXITINIB AND RETINOID TRETINOIN DECREASES PROLIFERATION AND HIGH-RISK NEOPLASTIC SUBPOPULATION PROPORTIONS PFA EPENDYMOMA
title_full_unstemmed EPEN-08. COMBINED PDGFR INHIBITOR AXITINIB AND RETINOID TRETINOIN DECREASES PROLIFERATION AND HIGH-RISK NEOPLASTIC SUBPOPULATION PROPORTIONS PFA EPENDYMOMA
title_short EPEN-08. COMBINED PDGFR INHIBITOR AXITINIB AND RETINOID TRETINOIN DECREASES PROLIFERATION AND HIGH-RISK NEOPLASTIC SUBPOPULATION PROPORTIONS PFA EPENDYMOMA
title_sort epen-08. combined pdgfr inhibitor axitinib and retinoid tretinoin decreases proliferation and high-risk neoplastic subpopulation proportions pfa ependymoma
topic Final Category: Ependymoma - EPEN
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260112/
http://dx.doi.org/10.1093/neuonc/noad073.112
work_keys_str_mv AT donsonandrew epen08combinedpdgfrinhibitoraxitinibandretinoidtretinoindecreasesproliferationandhighriskneoplasticsubpopulationproportionspfaependymoma
AT grimaldoenrique epen08combinedpdgfrinhibitoraxitinibandretinoidtretinoindecreasesproliferationandhighriskneoplasticsubpopulationproportionspfaependymoma
AT riemondykent epen08combinedpdgfrinhibitoraxitinibandretinoidtretinoindecreasesproliferationandhighriskneoplasticsubpopulationproportionspfaependymoma
AT griesingerandrea epen08combinedpdgfrinhibitoraxitinibandretinoidtretinoindecreasesproliferationandhighriskneoplasticsubpopulationproportionspfaependymoma
AT amanivladimir epen08combinedpdgfrinhibitoraxitinibandretinoidtretinoindecreasesproliferationandhighriskneoplasticsubpopulationproportionspfaependymoma
AT bruntbreauna epen08combinedpdgfrinhibitoraxitinibandretinoidtretinoindecreasesproliferationandhighriskneoplasticsubpopulationproportionspfaependymoma
AT pierceangela epen08combinedpdgfrinhibitoraxitinibandretinoidtretinoindecreasesproliferationandhighriskneoplasticsubpopulationproportionspfaependymoma
AT foremannicholas epen08combinedpdgfrinhibitoraxitinibandretinoidtretinoindecreasesproliferationandhighriskneoplasticsubpopulationproportionspfaependymoma