BET bromodomain inhibition of MYC-amplified medulloblastoma

Pratiti Bandopadhayay, Guillaume Bergthold, Brian Nguyen, Simone Schubert, Sharareh Gholamin, Yujie Tang, Sara Bolin, Steven E. Schumacher, Rhamy Zeid, Sabran Masoud, Furong Yu, Nujsaubnusi Vue, William J. Gibson, Brenton R. Paolella, Siddhartha S. Mitra, Samuel H. Cheshier, Jun Qi, Kun Wei Liu, Robert Wechsler-Reya, William A. Weiss & 5 others Fredrik J. Swartling, Mark W. Kieran, James E. Bradner, Rameen Beroukhim, Yoon-Jae Cho

Research output: Contribution to journalArticle

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Abstract

Purpose: MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. Experimental Design: We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patientand genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC orMYCN. We also assessed the effect of JQ1 onMYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Results: Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. Conclusion: JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

Original languageEnglish (US)
Pages (from-to)912-925
Number of pages14
JournalClinical Cancer Research
Volume20
Issue number4
DOIs
StatePublished - Feb 26 2014
Externally publishedYes

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Medulloblastoma
Heterografts
Cell Survival
Apoptosis
Neoplasms
Cell Cycle
Research Design
Down-Regulation
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bandopadhayay, P., Bergthold, G., Nguyen, B., Schubert, S., Gholamin, S., Tang, Y., ... Cho, Y-J. (2014). BET bromodomain inhibition of MYC-amplified medulloblastoma. Clinical Cancer Research, 20(4), 912-925. https://doi.org/10.1158/1078-0432.CCR-13-2281

BET bromodomain inhibition of MYC-amplified medulloblastoma. / Bandopadhayay, Pratiti; Bergthold, Guillaume; Nguyen, Brian; Schubert, Simone; Gholamin, Sharareh; Tang, Yujie; Bolin, Sara; Schumacher, Steven E.; Zeid, Rhamy; Masoud, Sabran; Yu, Furong; Vue, Nujsaubnusi; Gibson, William J.; Paolella, Brenton R.; Mitra, Siddhartha S.; Cheshier, Samuel H.; Qi, Jun; Liu, Kun Wei; Wechsler-Reya, Robert; Weiss, William A.; Swartling, Fredrik J.; Kieran, Mark W.; Bradner, James E.; Beroukhim, Rameen; Cho, Yoon-Jae.

In: Clinical Cancer Research, Vol. 20, No. 4, 26.02.2014, p. 912-925.

Research output: Contribution to journalArticle

Bandopadhayay, P, Bergthold, G, Nguyen, B, Schubert, S, Gholamin, S, Tang, Y, Bolin, S, Schumacher, SE, Zeid, R, Masoud, S, Yu, F, Vue, N, Gibson, WJ, Paolella, BR, Mitra, SS, Cheshier, SH, Qi, J, Liu, KW, Wechsler-Reya, R, Weiss, WA, Swartling, FJ, Kieran, MW, Bradner, JE, Beroukhim, R & Cho, Y-J 2014, 'BET bromodomain inhibition of MYC-amplified medulloblastoma', Clinical Cancer Research, vol. 20, no. 4, pp. 912-925. https://doi.org/10.1158/1078-0432.CCR-13-2281
Bandopadhayay P, Bergthold G, Nguyen B, Schubert S, Gholamin S, Tang Y et al. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clinical Cancer Research. 2014 Feb 26;20(4):912-925. https://doi.org/10.1158/1078-0432.CCR-13-2281
Bandopadhayay, Pratiti ; Bergthold, Guillaume ; Nguyen, Brian ; Schubert, Simone ; Gholamin, Sharareh ; Tang, Yujie ; Bolin, Sara ; Schumacher, Steven E. ; Zeid, Rhamy ; Masoud, Sabran ; Yu, Furong ; Vue, Nujsaubnusi ; Gibson, William J. ; Paolella, Brenton R. ; Mitra, Siddhartha S. ; Cheshier, Samuel H. ; Qi, Jun ; Liu, Kun Wei ; Wechsler-Reya, Robert ; Weiss, William A. ; Swartling, Fredrik J. ; Kieran, Mark W. ; Bradner, James E. ; Beroukhim, Rameen ; Cho, Yoon-Jae. / BET bromodomain inhibition of MYC-amplified medulloblastoma. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 4. pp. 912-925.
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T1 - BET bromodomain inhibition of MYC-amplified medulloblastoma

AU - Bandopadhayay, Pratiti

AU - Bergthold, Guillaume

AU - Nguyen, Brian

AU - Schubert, Simone

AU - Gholamin, Sharareh

AU - Tang, Yujie

AU - Bolin, Sara

AU - Schumacher, Steven E.

AU - Zeid, Rhamy

AU - Masoud, Sabran

AU - Yu, Furong

AU - Vue, Nujsaubnusi

AU - Gibson, William J.

AU - Paolella, Brenton R.

AU - Mitra, Siddhartha S.

AU - Cheshier, Samuel H.

AU - Qi, Jun

AU - Liu, Kun Wei

AU - Wechsler-Reya, Robert

AU - Weiss, William A.

AU - Swartling, Fredrik J.

AU - Kieran, Mark W.

AU - Bradner, James E.

AU - Beroukhim, Rameen

AU - Cho, Yoon-Jae

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N2 - Purpose: MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. Experimental Design: We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patientand genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC orMYCN. We also assessed the effect of JQ1 onMYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Results: Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. Conclusion: JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

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