A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma
©2018 American Association for Cancer Research..
PURPOSE: Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup medulloblastoma driven by TRP53 mutations is essentially lethal. Casein kinase 1α (CK1α) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a second-generation CK1α activator against TRP53-mutant, MYCN-amplified medulloblastoma.
EXPERIMENTAL DESIGN: The ability of this CK1α activator to block SHH signaling was determined in vitro using GLI reporter cells, granular precursor primary cultures, and PATCHED1 (PTCH1)-mutant sphere cultures. While in vivo efficacy was tested using 2 different medulloblastoma mouse models: PTCH1 and ND2:SMOA1. Finally, the clinical relevance of CK1α activators was demonstrated using a TRP53-mutant, MYCN-amplified patient-derived xenograft.
RESULTS: SSTC3 inhibited SHH activity in vitro, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH medulloblastoma. SSTC3 accumulated in the brain, inhibited growth of SHH medulloblastoma tumors, and blocked metastases in a genetically engineered vismodegib-resistant mouse model of SHH medulloblastoma. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derived TRP53-mutant, MYCN-amplified, SHH subgroup medulloblastoma xenografts, increasing overall survival.
CONCLUSIONS: Using a newly described small-molecule, SSTC3, we show that CK1a activators could address a significant unmet clinical need for patients with SMO inhibitor-resistant medulloblastoma, including those harboring mutations in TRP53.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
|---|---|
| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 25(2019), 4 vom: 15. Feb., Seite 1379-1388 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Rodriguez-Blanco, Jezabel [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 20.04.2020 Date Revised 20.04.2020 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1158/1078-0432.CCR-18-1319 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM291181724 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM291181724 | ||
| 003 | DE-627 | ||
| 005 | 20231225070332.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/1078-0432.CCR-18-1319 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0970.xml |
| 035 | |a (DE-627)NLM291181724 | ||
| 035 | |a (NLM)30487124 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Rodriguez-Blanco, Jezabel |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 20.04.2020 | ||
| 500 | |a Date Revised 20.04.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2018 American Association for Cancer Research. | ||
| 520 | |a PURPOSE: Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup medulloblastoma driven by TRP53 mutations is essentially lethal. Casein kinase 1α (CK1α) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a second-generation CK1α activator against TRP53-mutant, MYCN-amplified medulloblastoma | ||
| 520 | |a EXPERIMENTAL DESIGN: The ability of this CK1α activator to block SHH signaling was determined in vitro using GLI reporter cells, granular precursor primary cultures, and PATCHED1 (PTCH1)-mutant sphere cultures. While in vivo efficacy was tested using 2 different medulloblastoma mouse models: PTCH1 and ND2:SMOA1. Finally, the clinical relevance of CK1α activators was demonstrated using a TRP53-mutant, MYCN-amplified patient-derived xenograft | ||
| 520 | |a RESULTS: SSTC3 inhibited SHH activity in vitro, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH medulloblastoma. SSTC3 accumulated in the brain, inhibited growth of SHH medulloblastoma tumors, and blocked metastases in a genetically engineered vismodegib-resistant mouse model of SHH medulloblastoma. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derived TRP53-mutant, MYCN-amplified, SHH subgroup medulloblastoma xenografts, increasing overall survival | ||
| 520 | |a CONCLUSIONS: Using a newly described small-molecule, SSTC3, we show that CK1a activators could address a significant unmet clinical need for patients with SMO inhibitor-resistant medulloblastoma, including those harboring mutations in TRP53 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a 4-(N-methyl-N-(4-(trifluoromethyl)phenyl)sulfamoyl) benzoic acid |2 NLM | |
| 650 | 7 | |a Anilides |2 NLM | |
| 650 | 7 | |a Benzoates |2 NLM | |
| 650 | 7 | |a HhAntag691 |2 NLM | |
| 650 | 7 | |a MYCN protein, mouse |2 NLM | |
| 650 | 7 | |a N-Myc Proto-Oncogene Protein |2 NLM | |
| 650 | 7 | |a Pyridines |2 NLM | |
| 650 | 7 | |a Smo protein, mouse |2 NLM | |
| 650 | 7 | |a Smoothened Receptor |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a Zinc Finger Protein GLI1 |2 NLM | |
| 650 | 7 | |a Casein Kinase Ialpha |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 700 | 1 | |a Li, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Orton, Darren |e verfasserin |4 aut | |
| 700 | 1 | |a Collins, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Kasahara, Noriyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Ayad, Nagi G |e verfasserin |4 aut | |
| 700 | 1 | |a McCrea, Heather J |e verfasserin |4 aut | |
| 700 | 1 | |a Roussel, Martine F |e verfasserin |4 aut | |
| 700 | 1 | |a Weiss, William A |e verfasserin |4 aut | |
| 700 | 1 | |a Capobianco, Anthony J |e verfasserin |4 aut | |
| 700 | 1 | |a Robbins, David J |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Clinical cancer research : an official journal of the American Association for Cancer Research |d 1995 |g 25(2019), 4 vom: 15. Feb., Seite 1379-1388 |w (DE-627)NLM09444479X |x 1557-3265 |7 nnns |
| 773 | 1 | 8 | |g volume:25 |g year:2019 |g number:4 |g day:15 |g month:02 |g pages:1379-1388 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/1078-0432.CCR-18-1319 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 25 |j 2019 |e 4 |b 15 |c 02 |h 1379-1388 | ||