10 results on '"Hakkert, Anne"'
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2. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma
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Chesler, Louis, Poon, Eva, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thwway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E., Licciardello, Marco P., Sbirkov, Yordan, Lazaro, Glori, and Calton, Elizabeth
- Subjects
Kinase inhibitors -- Usage ,Transcription factors -- Health aspects ,Neuroblastoma -- Drug therapy ,Health care industry - Abstract
The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYCO65 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYOV-amplified neuroblastoma via multiple mechanisms. CDK9--a component of the transcription elongation complex P-TEFb--bound to the MYCAf-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCAf-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYCO65. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYCO65. CYCO65, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCAf-amplified neuroblastoma., Introduction The prominent role of Myc family protooncogene transcription factors (TFs) (MYC, MYCN, MYCL) in the genesis of adult and childhood cancers makes these TFs attractive targets for drug discovery [...]
- Published
- 2020
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3. Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma
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van den Boogaard, Marlinde L, Oka, Rurika, Hakkert, Anne, Schild, Linda, Ebus, Marli E, van Gerven, Michael R, Zwijnenburg, Danny A, Molenaar, Piet, Hoyng, Lieke L, Dolman, M Emmy M, Essing, Anke H W, Koopmans, Bianca, Helleday, Thomas, Drost, Jarno, van Boxtel, Ruben, Versteeg, Rogier, Koster, Jan, Molenaar, Jan J, van den Boogaard, Marlinde L, Oka, Rurika, Hakkert, Anne, Schild, Linda, Ebus, Marli E, van Gerven, Michael R, Zwijnenburg, Danny A, Molenaar, Piet, Hoyng, Lieke L, Dolman, M Emmy M, Essing, Anke H W, Koopmans, Bianca, Helleday, Thomas, Drost, Jarno, van Boxtel, Ruben, Versteeg, Rogier, Koster, Jan, and Molenaar, Jan J
- Abstract
Neuroblastomas are childhood tumors with frequent fatal relapses after induction treatment, which is related to tumor evolution with additional genomic events. Our whole-genome sequencing data analysis revealed a high frequency of somatic cytosine > adenine (C > A) substitutions in primary neuroblastoma tumors, which was associated with poor survival. We showed that increased levels of C > A substitutions correlate with copy number loss (CNL) of OGG1 or MUTYH Both genes encode DNA glycosylases that recognize 8-oxo-guanine (8-oxoG) lesions as a first step of 8-oxoG repair. Tumor organoid models with CNL of OGG1 or MUTYH show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of MUTYH and OGG1 in neuroblastoma cells. Whole-genome sequencing of single-cell OGG1 and MUTYH knockout clones identified an increased accumulation of C > A substitutions. Mutational signature analysis of these OGG1 and MUTYH knockout clones revealed enrichment for C > A signatures 18 and 36, respectively. Clustering analysis showed that the knockout clones group together with tumors containing OGG1 or MUTYH CNL. In conclusion, we demonstrate that defects in 8-oxoG repair cause accumulation of C > A substitutions in neuroblastoma, which contributes to mutagenesis and tumor evolution.
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- 2021
4. Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma
- Author
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Afd Pharmaceutics, Pharmaceutics, van den Boogaard, Marlinde L, Oka, Rurika, Hakkert, Anne, Schild, Linda, Ebus, Marli E, van Gerven, Michael R, Zwijnenburg, Danny A, Molenaar, Piet, Hoyng, Lieke L, Dolman, M Emmy M, Essing, Anke H W, Koopmans, Bianca, Helleday, Thomas, Drost, Jarno, van Boxtel, Ruben, Versteeg, Rogier, Koster, Jan, Molenaar, Jan J, Afd Pharmaceutics, Pharmaceutics, van den Boogaard, Marlinde L, Oka, Rurika, Hakkert, Anne, Schild, Linda, Ebus, Marli E, van Gerven, Michael R, Zwijnenburg, Danny A, Molenaar, Piet, Hoyng, Lieke L, Dolman, M Emmy M, Essing, Anke H W, Koopmans, Bianca, Helleday, Thomas, Drost, Jarno, van Boxtel, Ruben, Versteeg, Rogier, Koster, Jan, and Molenaar, Jan J
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- 2021
5. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma
- Author
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Poon, Evon, primary, Liang, Tong, additional, Jamin, Yann, additional, Walz, Susanne, additional, Kwok, Colin, additional, Hakkert, Anne, additional, Barker, Karen, additional, Urban, Zuzanna, additional, Thway, Khin, additional, Zeid, Rhamy, additional, Hallsworth, Albert, additional, Box, Gary, additional, Ebus, Marli E., additional, Licciardello, Marco P., additional, Sbirkov, Yordan, additional, Lazaro, Glori, additional, Calton, Elizabeth, additional, Costa, Barbara M., additional, Valenti, Melanie, additional, De Haven Brandon, Alexis, additional, Webber, Hannah, additional, Tardif, Nicolas, additional, Almeida, Gilberto S., additional, Christova, Rossitza, additional, Boysen, Gunther, additional, Richards, Mark W., additional, Barone, Giuseppe, additional, Ford, Anthony, additional, Bayliss, Richard, additional, Clarke, Paul A., additional, De Bono, Johann, additional, Gray, Nathanael S., additional, Blagg, Julian, additional, Robinson, Simon P., additional, Eccles, Suzanne A., additional, Zheleva, Daniella, additional, Bradner, James E., additional, Molenaar, Jan, additional, Vivanco, Igor, additional, Eilers, Martin, additional, Workman, Paul, additional, Lin, Charles Y., additional, and Chesler, Louis, additional
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- 2020
- Full Text
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6. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma
- Author
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Poon, Evon, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E, Licciardello, Marco P, Sbirkov, Yordan, Lazaro, Glori, Calton, Elizabeth, Costa, Barbara M, Valenti, Melanie, De Haven Brandon, Alexis, Webber, Hannah, Tardif, Nicolas, Almeida, Gilberto S, Christova, Rossitza, Boysen, Gunther, Richards, Mark W, Barone, Giuseppe, Ford, Anthony, Bayliss, Richard, Clarke, Paul A, De Bono, Johann, Gray, Nathanael S, Blagg, Julian, Robinson, Simon P, Eccles, Suzanne A, Zheleva, Daniella, Bradner, James E, Molenaar, Jan, Vivanco, Igor, Eilers, Martin, Workman, Paul, Lin, Charles Y, Chesler, Louis, Poon, Evon, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E, Licciardello, Marco P, Sbirkov, Yordan, Lazaro, Glori, Calton, Elizabeth, Costa, Barbara M, Valenti, Melanie, De Haven Brandon, Alexis, Webber, Hannah, Tardif, Nicolas, Almeida, Gilberto S, Christova, Rossitza, Boysen, Gunther, Richards, Mark W, Barone, Giuseppe, Ford, Anthony, Bayliss, Richard, Clarke, Paul A, De Bono, Johann, Gray, Nathanael S, Blagg, Julian, Robinson, Simon P, Eccles, Suzanne A, Zheleva, Daniella, Bradner, James E, Molenaar, Jan, Vivanco, Igor, Eilers, Martin, Workman, Paul, Lin, Charles Y, and Chesler, Louis
- Abstract
The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.
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- 2020
7. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma
- Author
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UU BETA RESEARCH, Poon, Evon, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E, Licciardello, Marco P, Sbirkov, Yordan, Lazaro, Glori, Calton, Elizabeth, Costa, Barbara M, Valenti, Melanie, De Haven Brandon, Alexis, Webber, Hannah, Tardif, Nicolas, Almeida, Gilberto S, Christova, Rossitza, Boysen, Gunther, Richards, Mark W, Barone, Giuseppe, Ford, Anthony, Bayliss, Richard, Clarke, Paul A, De Bono, Johann, Gray, Nathanael S, Blagg, Julian, Robinson, Simon P, Eccles, Suzanne A, Zheleva, Daniella, Bradner, James E, Molenaar, Jan, Vivanco, Igor, Eilers, Martin, Workman, Paul, Lin, Charles Y, Chesler, Louis, UU BETA RESEARCH, Poon, Evon, Liang, Tong, Jamin, Yann, Walz, Susanne, Kwok, Colin, Hakkert, Anne, Barker, Karen, Urban, Zuzanna, Thway, Khin, Zeid, Rhamy, Hallsworth, Albert, Box, Gary, Ebus, Marli E, Licciardello, Marco P, Sbirkov, Yordan, Lazaro, Glori, Calton, Elizabeth, Costa, Barbara M, Valenti, Melanie, De Haven Brandon, Alexis, Webber, Hannah, Tardif, Nicolas, Almeida, Gilberto S, Christova, Rossitza, Boysen, Gunther, Richards, Mark W, Barone, Giuseppe, Ford, Anthony, Bayliss, Richard, Clarke, Paul A, De Bono, Johann, Gray, Nathanael S, Blagg, Julian, Robinson, Simon P, Eccles, Suzanne A, Zheleva, Daniella, Bradner, James E, Molenaar, Jan, Vivanco, Igor, Eilers, Martin, Workman, Paul, Lin, Charles Y, and Chesler, Louis
- Published
- 2020
8. Abstract A26: High frequency of Cytosine to Adenine mutations in neuroblastoma correlates with genomic aberrations in 8-Oxo-Guanine repair pathway
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Hakkert, Anne, primary, Ebus, Marli E., additional, Versteeg, Rogier, additional, Huib, Caron N., additional, Koster, Jan, additional, and Molenaar, Jan J., additional
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- 2017
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9. Abstract 2980: Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations
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Oldridge, Derek A., primary, Eleveld, Thomas F., additional, Bernard, Virginie, additional, Koster, Jan, additional, Daage, Leo C., additional, Diskin, Sharon J., additional, Schild, Linda, additional, Bentahar, Nadia B., additional, Bellini, Angela, additional, Chicard, Mathieu, additional, Lapouble, Eve, additional, Combaret, Valérie, additional, Legoix-Né, Patricia, additional, Michon, Jean, additional, Pugh, Trevor J., additional, Hart, Lori S., additional, Rader, JulieAnn, additional, Attiyeh, Edward F., additional, Wei, Jun S., additional, Zhang, Shile, additional, Naranjo, Arlene, additional, Gastier-Foster, Julie M., additional, Hogarty, Michael D., additional, Smith, Malcolm A., additional, Auvil, Jaime G., additional, Watkins, Thomas B. K., additional, Zwijnenburg, Danny A., additional, Ebus, Marli E., additional, van Sluis, Peter, additional, Hakkert, Anne, additional, van Wezel, Esther, additional, van der Schoot, C. Ellen, additional, Westerhout, Ellen M., additional, Schulte, Johannes H., additional, Tytgat, Godelieve A., additional, Dolman, M. Emmy M., additional, Janoueix-Lerosey, Isabelle, additional, Gerhard, Daniela S., additional, Caron, Huib N., additional, Delattre, Olivier, additional, Khan, Javed, additional, Versteeg, Rogier, additional, Schleiermacher, Gudrun, additional, Maris, John M., additional, and Molenaar, Jan J., additional
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- 2015
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10. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations
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Eleveld, Thomas F, primary, Oldridge, Derek A, additional, Bernard, Virginie, additional, Koster, Jan, additional, Daage, Leo Colmet, additional, Diskin, Sharon J, additional, Schild, Linda, additional, Bentahar, Nadia Bessoltane, additional, Bellini, Angela, additional, Chicard, Mathieu, additional, Lapouble, Eve, additional, Combaret, Valérie, additional, Legoix-Né, Patricia, additional, Michon, Jean, additional, Pugh, Trevor J, additional, Hart, Lori S, additional, Rader, JulieAnn, additional, Attiyeh, Edward F, additional, Wei, Jun S, additional, Zhang, Shile, additional, Naranjo, Arlene, additional, Gastier-Foster, Julie M, additional, Hogarty, Michael D, additional, Asgharzadeh, Shahab, additional, Smith, Malcolm A, additional, Guidry Auvil, Jaime M, additional, Watkins, Thomas B K, additional, Zwijnenburg, Danny A, additional, Ebus, Marli E, additional, van Sluis, Peter, additional, Hakkert, Anne, additional, van Wezel, Esther, additional, van der Schoot, C Ellen, additional, Westerhout, Ellen M, additional, Schulte, Johannes H, additional, Tytgat, Godelieve A, additional, Dolman, M Emmy M, additional, Janoueix-Lerosey, Isabelle, additional, Gerhard, Daniela S, additional, Caron, Huib N, additional, Delattre, Olivier, additional, Khan, Javed, additional, Versteeg, Rogier, additional, Schleiermacher, Gudrun, additional, Molenaar, Jan J, additional, and Maris, John M, additional
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- 2015
- Full Text
- View/download PDF
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