Downregulation of MYCN through PI3K inhibition in mouse models of pediatric neural cancer
The MYCN proto-oncogene is associated with poor outcome across a broad range of pediatric tumors. While amplification of MYCN drives subsets of high risk neuroblastoma and medulloblastoma, dysregulation of MYCN in medulloblastoma (in the absence of amplification) also contributes to pathogenesis. Si...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2015-05-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fonc.2015.00111/full |
| _version_ | 1818558659092807680 |
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| author | Tene Aneka Cage Yvan eChanthery Yvan eChanthery Louis eChesler Matthew eGrimmer Matthew eGrimmer Zachary eKnight Kevan eShokat William A Weiss William A Weiss William A Weiss William A Weiss W. Clay Gustafson W. Clay Gustafson |
| author_facet | Tene Aneka Cage Yvan eChanthery Yvan eChanthery Louis eChesler Matthew eGrimmer Matthew eGrimmer Zachary eKnight Kevan eShokat William A Weiss William A Weiss William A Weiss William A Weiss W. Clay Gustafson W. Clay Gustafson |
| author_sort | Tene Aneka Cage |
| collection | DOAJ |
| description | The MYCN proto-oncogene is associated with poor outcome across a broad range of pediatric tumors. While amplification of MYCN drives subsets of high risk neuroblastoma and medulloblastoma, dysregulation of MYCN in medulloblastoma (in the absence of amplification) also contributes to pathogenesis. Since PI3K stabilizes MYCN, we have used inhibitors of PI3K to drive degradation. In this study, we show PI3K inhibitors by themselves induce cell cycle arrest, with modest induction of apoptosis. In screening inhibitors of PI3K against MYCN, we identified PIK-75 and its derivative, PW-12, inhibitors of both PI3K and of protein kinases, to be highly effective in destabilizing MYCN. To determine the effects of PW-12 treatment in-vivo, we analyzed a genetically engineered mouse model for MYCN-driven neuroblastoma and a model of MYCN-driven medulloblastoma. PW-12 showed significant activity in both models, inducing vascular collapse and regression of medulloblastoma with prominent apoptosis in both models. These results demonstrate that inhibitors of lipid and protein kinases can drive apoptosis in MYCN-driven cancers and support the importance of MYCN as a therapeutic target. |
| first_indexed | 2024-12-14T00:15:10Z |
| format | Article |
| id | doaj.art-4a9deb12ba5643ba98a3967e5b30168c |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-14T00:15:10Z |
| publishDate | 2015-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-4a9deb12ba5643ba98a3967e5b30168c2022-12-21T23:25:34ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2015-05-01510.3389/fonc.2015.00111136901Downregulation of MYCN through PI3K inhibition in mouse models of pediatric neural cancerTene Aneka Cage0Yvan eChanthery1Yvan eChanthery2Louis eChesler3Matthew eGrimmer4Matthew eGrimmer5Zachary eKnight6Kevan eShokat7William A Weiss8William A Weiss9William A Weiss10William A Weiss11W. Clay Gustafson12W. Clay Gustafson13University of California San FranciscoUniversity of California San FranciscoSanta Clara UniversityThe Institute of Cancer ResearchUniversity of California San FranciscoUniversity of California San FranciscoUniversity of California San FranciscoUniversity of California San FranciscoUniversity of California San FranciscoUniversity of California San FranciscoUniversity of California San FranciscoUniversity of California San FranciscoUniversity of California San FranciscoUniversity of California San FranciscoThe MYCN proto-oncogene is associated with poor outcome across a broad range of pediatric tumors. While amplification of MYCN drives subsets of high risk neuroblastoma and medulloblastoma, dysregulation of MYCN in medulloblastoma (in the absence of amplification) also contributes to pathogenesis. Since PI3K stabilizes MYCN, we have used inhibitors of PI3K to drive degradation. In this study, we show PI3K inhibitors by themselves induce cell cycle arrest, with modest induction of apoptosis. In screening inhibitors of PI3K against MYCN, we identified PIK-75 and its derivative, PW-12, inhibitors of both PI3K and of protein kinases, to be highly effective in destabilizing MYCN. To determine the effects of PW-12 treatment in-vivo, we analyzed a genetically engineered mouse model for MYCN-driven neuroblastoma and a model of MYCN-driven medulloblastoma. PW-12 showed significant activity in both models, inducing vascular collapse and regression of medulloblastoma with prominent apoptosis in both models. These results demonstrate that inhibitors of lipid and protein kinases can drive apoptosis in MYCN-driven cancers and support the importance of MYCN as a therapeutic target.http://journal.frontiersin.org/Journal/10.3389/fonc.2015.00111/fullMedulloblastomaNeuroblastomaCancerCell signalingpediatricmTOR |
| spellingShingle | Tene Aneka Cage Yvan eChanthery Yvan eChanthery Louis eChesler Matthew eGrimmer Matthew eGrimmer Zachary eKnight Kevan eShokat William A Weiss William A Weiss William A Weiss William A Weiss W. Clay Gustafson W. Clay Gustafson Downregulation of MYCN through PI3K inhibition in mouse models of pediatric neural cancer Frontiers in Oncology Medulloblastoma Neuroblastoma Cancer Cell signaling pediatric mTOR |
| title | Downregulation of MYCN through PI3K inhibition in mouse models of pediatric neural cancer |
| title_full | Downregulation of MYCN through PI3K inhibition in mouse models of pediatric neural cancer |
| title_fullStr | Downregulation of MYCN through PI3K inhibition in mouse models of pediatric neural cancer |
| title_full_unstemmed | Downregulation of MYCN through PI3K inhibition in mouse models of pediatric neural cancer |
| title_short | Downregulation of MYCN through PI3K inhibition in mouse models of pediatric neural cancer |
| title_sort | downregulation of mycn through pi3k inhibition in mouse models of pediatric neural cancer |
| topic | Medulloblastoma Neuroblastoma Cancer Cell signaling pediatric mTOR |
| url | http://journal.frontiersin.org/Journal/10.3389/fonc.2015.00111/full |
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