Publications
2025
Trimpont, Maaike Van; Schalk, Amanda M.; Hofkens, Kenneth; Peeters, Evelien; T'Sas, Sara; Vandemeulebroecke, Katrien; Su, Ying; Loera, Ashley De; Garcia, Alyssa; Chen, Hui; Lammens, Tim; Vlierberghe, Pieter Van; Goossens, Steven; Lavie, Arnon
A human-like glutaminase-free asparaginase is highly efficacious in ASNSlow leukemia and solid cancer mouse xenograft models Journal Article
In: Cancer Letters, vol. 611, 2025, ISSN: 0304-3835.
@article{VanTrimpont2025,
title = {A human-like glutaminase-free asparaginase is highly efficacious in ASNSlow leukemia and solid cancer mouse xenograft models},
author = {Maaike Van Trimpont and Amanda M. Schalk and Kenneth Hofkens and Evelien Peeters and Sara T'Sas and Katrien Vandemeulebroecke and Ying Su and Ashley De Loera and Alyssa Garcia and Hui Chen and Tim Lammens and Pieter Van Vlierberghe and Steven Goossens and Arnon Lavie},
doi = {10.1016/j.canlet.2024.217404},
issn = {0304-3835},
year = {2025},
date = {2025-02-00},
urldate = {2025-02-00},
journal = {Cancer Letters},
volume = {611},
publisher = {Elsevier BV},
abstract = {L-asparaginase (L-ASNase) is crucial in treating pediatric acute lymphoblastic leukemia (ALL), but its use is hampered by side effects from the immunogenicity and L-glutaminase (L-GLNase) co-activity of FDA-approved bacterial L-ASNases, often leading to treatment discontinuation and poor outcomes. The toxicity of these L-ASNases makes them especially challenging to use in adult cancer patients. To overcome these issues, we developed EBD-200, a humanized guinea pig L-ASNase with low Km and no L-GLNase activity, eliminating glutamine-related toxicity. EBD-200 showed comparable anti-cancer effects to PEGylated L-ASNase in ASNSlow ALL, melanoma and liver cancer models, with improved tolerability. Its potent anti-cancer efficacy and enhanced safety profile suggest that EBD-200 could benefit ALL patients and broaden treatment options for ASNSlow solid cancers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
L-asparaginase (L-ASNase) is crucial in treating pediatric acute lymphoblastic leukemia (ALL), but its use is hampered by side effects from the immunogenicity and L-glutaminase (L-GLNase) co-activity of FDA-approved bacterial L-ASNases, often leading to treatment discontinuation and poor outcomes. The toxicity of these L-ASNases makes them especially challenging to use in adult cancer patients. To overcome these issues, we developed EBD-200, a humanized guinea pig L-ASNase with low Km and no L-GLNase activity, eliminating glutamine-related toxicity. EBD-200 showed comparable anti-cancer effects to PEGylated L-ASNase in ASNSlow ALL, melanoma and liver cancer models, with improved tolerability. Its potent anti-cancer efficacy and enhanced safety profile suggest that EBD-200 could benefit ALL patients and broaden treatment options for ASNSlow solid cancers.
Vu, Hue; Peeters, Evelien; Hofkens, Kenneth; Vandemeulebroecke, Katrien; T'Sas, Sara; Martin, Charlotte; Ballet, Steven; Hoogenboom, Richard; Goossens, Steven; Lammens, Tim; Trimpont, Maaike Van; Madder, Annemieke
Peptide hydrogels as slow-release formulations of protein therapeutics: case study of asparaginase-loaded hydrogels Journal Article
In: Biomater. Sci., 2025, ISSN: 2047-4849.
@article{Vu2025,
title = {Peptide hydrogels as slow-release formulations of protein therapeutics: case study of asparaginase-loaded hydrogels},
author = {Hue Vu and Evelien Peeters and Kenneth Hofkens and Katrien Vandemeulebroecke and Sara T'Sas and Charlotte Martin and Steven Ballet and Richard Hoogenboom and Steven Goossens and Tim Lammens and Maaike Van Trimpont and Annemieke Madder},
doi = {10.1039/d5bm00138b},
issn = {2047-4849},
year = {2025},
date = {2025-00-00},
urldate = {2025-00-00},
journal = {Biomater. Sci.},
publisher = {Royal Society of Chemistry (RSC)},
abstract = {In this study, hexamer peptide-based hydrogels were loaded with different model protein cargos and the release profiles investigated to explore the balance between injectability and loading capacity permitting the release of a therapeutically relevant dose. We demonstrate that the release of protein cargos from our hexamer peptide hydrogels depends on the stability of the hydrogel network, the mobility of the cargo to diffuse out of the network, and the interaction between the hydrogel network and the cargo. For the first time, our peptide hydrogels were used to develop an injectable sustained release formulation of a therapeutic enzyme, namely Erwinase®, an FDA-approved asparaginase for the treatment of acute lymphoblastic leukemia. We show that the current hexamer peptide-based hydrogels allow sufficient protein loading and sustained release of the fully active asparaginase enzyme both in vitro and in vivo. Altogether, this study describes how peptide hydrogels can be exploited to provide injectable slow-release formulations of biologics, including enzyme therapeutics, to enhance their clinical applicability.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In this study, hexamer peptide-based hydrogels were loaded with different model protein cargos and the release profiles investigated to explore the balance between injectability and loading capacity permitting the release of a therapeutically relevant dose. We demonstrate that the release of protein cargos from our hexamer peptide hydrogels depends on the stability of the hydrogel network, the mobility of the cargo to diffuse out of the network, and the interaction between the hydrogel network and the cargo. For the first time, our peptide hydrogels were used to develop an injectable sustained release formulation of a therapeutic enzyme, namely Erwinase®, an FDA-approved asparaginase for the treatment of acute lymphoblastic leukemia. We show that the current hexamer peptide-based hydrogels allow sufficient protein loading and sustained release of the fully active asparaginase enzyme both in vitro and in vivo. Altogether, this study describes how peptide hydrogels can be exploited to provide injectable slow-release formulations of biologics, including enzyme therapeutics, to enhance their clinical applicability.
2024
Demoen, Lisa; Matthijssens, Filip; Reunes, Lindy; Palhais, Bruno; Lintermans, Béatrice; T’Sas, Sara; Fijalkowski, Igor; Taminau, Joachim; Akele, Muluembet Z.; Belle, Siska Van; Taghon, Tom; Deforce, Dieter; Nieuwerburgh, Filip Van; Berx, Geert; Ntziachristos, Panagiotis; Debyser, Zeger; Durinck, Kaat; Pieters, Tim; Goossens, Steven; Vlierberghe, Pieter Van
A dual role for PSIP1/LEDGF in T cell acute lymphoblastic leukemia Journal Article
In: Sci. Adv., vol. 10, no. 44, 2024, ISSN: 2375-2548.
@article{Demoen2024,
title = {A dual role for PSIP1/LEDGF in T cell acute lymphoblastic leukemia},
author = {Lisa Demoen and Filip Matthijssens and Lindy Reunes and Bruno Palhais and Béatrice Lintermans and Sara T’Sas and Igor Fijalkowski and Joachim Taminau and Muluembet Z. Akele and Siska Van Belle and Tom Taghon and Dieter Deforce and Filip Van Nieuwerburgh and Geert Berx and Panagiotis Ntziachristos and Zeger Debyser and Kaat Durinck and Tim Pieters and Steven Goossens and Pieter Van Vlierberghe},
doi = {10.1126/sciadv.ado6765},
issn = {2375-2548},
year = {2024},
date = {2024-11-00},
journal = {Sci. Adv.},
volume = {10},
number = {44},
publisher = {American Association for the Advancement of Science (AAAS)},
abstract = {
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current intensified therapeutic protocols coincide with severe side effects, and no salvage therapy is available for primary therapy-resistant or relapsed patients. This highlights the need to identify new therapeutic targets in T-ALL. PSIP1, dispensable for normal hematopoiesis, is a dependency factor in
KMT2A
-rearranged myeloid leukemia. Nonetheless, loss-of-function mutations suggest a tumor suppressor role for PSIP1 in T-ALL. Here, we demonstrate that the loss of
Psip1
accelerates T-ALL initiation in mice which we correlated with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several T-ALL cell lines. In cell lines, PSIP1 down-regulation leads to a reduction of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and to a reduction in mitochondrial respiration. This indicates that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.
keywords = {},
pubstate = {published},
tppubtype = {article}
}
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current intensified therapeutic protocols coincide with severe side effects, and no salvage therapy is available for primary therapy-resistant or relapsed patients. This highlights the need to identify new therapeutic targets in T-ALL. PSIP1, dispensable for normal hematopoiesis, is a dependency factor in
-rearranged myeloid leukemia. Nonetheless, loss-of-function mutations suggest a tumor suppressor role for PSIP1 in T-ALL. Here, we demonstrate that the loss of
accelerates T-ALL initiation in mice which we correlated with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several T-ALL cell lines. In cell lines, PSIP1 down-regulation leads to a reduction of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and to a reduction in mitochondrial respiration. This indicates that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.
2023
Trimpont, M. Van; Schalk, A. M.; Visser, Y. De; Nguyen, H. A.; Reunes, L.; Vandemeulebroecke, K.; Peeters, E.; Su, Y.; Lee, H.; Lorenzi, P. L.; Chan, W. K.; Mondelaers, V.; Moerloose, B. De; Lammens, T.; Goossens, S.; Vlierberghe, P. Van; Lavie, A.
Stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia Journal Article
In: Haematologica, vol. 108, no. 2, pp. 409–419, 2023.
@article{pmid35979719,
title = {Stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia},
author = {M. Van Trimpont and A. M. Schalk and Y. De Visser and H. A. Nguyen and L. Reunes and K. Vandemeulebroecke and E. Peeters and Y. Su and H. Lee and P. L. Lorenzi and W. K. Chan and V. Mondelaers and B. De Moerloose and T. Lammens and S. Goossens and P. Van Vlierberghe and A. Lavie},
url = {https://doi.org/10.3324/haematol.2022.281390},
year = {2023},
date = {2023-02-01},
urldate = {2023-02-01},
journal = {Haematologica},
volume = {108},
number = {2},
pages = {409--419},
abstract = {Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.
Provez, L.; Putteman, T.; Landfors, M.; Roels, J.; Reunes, L.; T'Sas, S.; Loocke, W. Van; Lintermans, B.; Coninck, S. De; Thenoz, M.; Sleeckx, W.; lak, N.; Taghon, T.; Mansour, M. R.; Farah, N.; Norga, K.; Vandenberghe, P.; Kotecha, R. S.; Goossens, S.; Degerman, S.; Smedt, R. De; Vlierberghe, P. Van
Pre-Clinical Evaluation of the Hypomethylating Agent Decitabine for the Treatment of T-Cell Lymphoblastic Lymphoma Journal Article
In: Cancers, vol. 15, no. 3, 2023.
@article{pmid36765607,
title = {Pre-Clinical Evaluation of the Hypomethylating Agent Decitabine for the Treatment of T-Cell Lymphoblastic Lymphoma},
author = {L. Provez and T. Putteman and M. Landfors and J. Roels and L. Reunes and S. T'Sas and W. Van Loocke and B. Lintermans and S. De Coninck and M. Thenoz and W. Sleeckx and N. lak and T. Taghon and M. R. Mansour and N. Farah and K. Norga and P. Vandenberghe and R. S. Kotecha and S. Goossens and S. Degerman and R. De Smedt and P. Van Vlierberghe},
url = {https://doi.org/10.3390/cancers15030647},
year = {2023},
date = {2023-01-01},
urldate = {2023-01-01},
journal = {Cancers},
volume = {15},
number = {3},
abstract = {T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10-20% of patients still die from relapsed or refractory disease. Given this, the search toward less toxic anti-lymphoma therapies is ongoing. Here, we targeted the recently described DNA hypermethylated profile in T-LBL with the DNA hypomethylating agent decitabine. We evaluated the anti-lymphoma properties and downstream effects of decitabine, using patient derived xenograft (PDX) models. Decitabine treatment resulted in prolonged lymphoma-free survival in all T-LBL PDX models, which was associated with downregulation of the oncogenic MYC pathway. However, some PDX models showed more benefit of decitabine treatment compared to others. In more sensitive models, differentially methylated CpG regions resulted in more differentially expressed genes in open chromatin regions. This resulted in stronger downregulation of cell cycle genes and upregulation of immune response activating transcripts. Finally, we suggest a gene signature for high decitabine sensitivity in T-LBL. Altogether, we here delivered pre-clinical proof of the potential use of decitabine as a new therapeutic agent in T-LBL.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10-20% of patients still die from relapsed or refractory disease. Given this, the search toward less toxic anti-lymphoma therapies is ongoing. Here, we targeted the recently described DNA hypermethylated profile in T-LBL with the DNA hypomethylating agent decitabine. We evaluated the anti-lymphoma properties and downstream effects of decitabine, using patient derived xenograft (PDX) models. Decitabine treatment resulted in prolonged lymphoma-free survival in all T-LBL PDX models, which was associated with downregulation of the oncogenic MYC pathway. However, some PDX models showed more benefit of decitabine treatment compared to others. In more sensitive models, differentially methylated CpG regions resulted in more differentially expressed genes in open chromatin regions. This resulted in stronger downregulation of cell cycle genes and upregulation of immune response activating transcripts. Finally, we suggest a gene signature for high decitabine sensitivity in T-LBL. Altogether, we here delivered pre-clinical proof of the potential use of decitabine as a new therapeutic agent in T-LBL.
2022
Canté-Barrett, K.; Meijer, M. T.; Cordo', V.; Hagelaar, R.; Yang, W.; Yu, J.; Smits, W. K.; Nulle, M. E.; Jansen, J. P.; Pieters, R.; Yang, J. J.; Haigh, J. J.; Goossens, S.; Meijerink, J. P.
MEF2C opposes Notch in lymphoid lineage decision and drives leukemia in the thymus Journal Article
In: JCI Insight, vol. 7, no. 13, 2022.
@article{pmid35536646,
title = {MEF2C opposes Notch in lymphoid lineage decision and drives leukemia in the thymus},
author = {K. Canté-Barrett and M. T. Meijer and V. Cordo' and R. Hagelaar and W. Yang and J. Yu and W. K. Smits and M. E. Nulle and J. P. Jansen and R. Pieters and J. J. Yang and J. J. Haigh and S. Goossens and J. P. Meijerink},
url = {https://doi.org/10.1172/jci.insight.150363},
year = {2022},
date = {2022-07-01},
urldate = {2022-07-01},
journal = {JCI Insight},
volume = {7},
number = {13},
abstract = {Rearrangements that drive ectopic MEF2C expression have recurrently been found in patients with human early thymocyte progenitor acute lymphoblastic leukemia (ETP-ALL). Here, we show high levels of MEF2C expression in patients with ETP-ALL. Using both in vivo and in vitro models of ETP-ALL, we demonstrate that elevated MEF2C expression blocks NOTCH-induced T cell differentiation while promoting a B-lineage program. MEF2C activates a B cell transcriptional program in addition to RUNX1, GATA3, and LMO2; upregulates the IL-7R; and boosts cell survival by upregulation of BCL2. MEF2C and the Notch pathway, therefore, demarcate opposite regulators of B- or T-lineage choices, respectively. Enforced MEF2C expression in mouse or human progenitor cells effectively blocks early T cell differentiation and promotes the development of biphenotypic lymphoid tumors that coexpress CD3 and CD19, resembling human mixed phenotype acute leukemia. Salt-inducible kinase (SIK) inhibitors impair MEF2C activity and alleviate the T cell developmental block. Importantly, this sensitizes cells to prednisolone treatment. Therefore, SIK-inhibiting compounds such as dasatinib are potentially valuable additions to standard chemotherapy for human ETP-ALL.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Rearrangements that drive ectopic MEF2C expression have recurrently been found in patients with human early thymocyte progenitor acute lymphoblastic leukemia (ETP-ALL). Here, we show high levels of MEF2C expression in patients with ETP-ALL. Using both in vivo and in vitro models of ETP-ALL, we demonstrate that elevated MEF2C expression blocks NOTCH-induced T cell differentiation while promoting a B-lineage program. MEF2C activates a B cell transcriptional program in addition to RUNX1, GATA3, and LMO2; upregulates the IL-7R; and boosts cell survival by upregulation of BCL2. MEF2C and the Notch pathway, therefore, demarcate opposite regulators of B- or T-lineage choices, respectively. Enforced MEF2C expression in mouse or human progenitor cells effectively blocks early T cell differentiation and promotes the development of biphenotypic lymphoid tumors that coexpress CD3 and CD19, resembling human mixed phenotype acute leukemia. Salt-inducible kinase (SIK) inhibitors impair MEF2C activity and alleviate the T cell developmental block. Importantly, this sensitizes cells to prednisolone treatment. Therefore, SIK-inhibiting compounds such as dasatinib are potentially valuable additions to standard chemotherapy for human ETP-ALL.
Nunes, C.; Depestel, L.; Mus, L.; Keller, K. M.; Delhaye, L.; Louwagie, A.; Rishfi, M.; Whale, A.; Kara, N.; Andrews, S. R.; Cruz, F. Dela; You, D.; Siddiquee, A.; Cologna, C. T.; Craemer, S. De; Dolman, E.; Bartenhagen, C.; Vloed, F. De; Sanders, E.; Eggermont, A.; Bekaert, S. L.; Loocke, W. Van; Bek, J. W.; Dewyn, G.; Loontiens, S.; Isterdael, G. Van; Decaesteker, B.; Tilleman, L.; Nieuwerburgh, F. Van; Vermeirssen, V.; Neste, C. Van; Ghesquiere, B.; Goossens, S.; Eyckerman, S.; Preter, K. De; Fischer, M.; Houseley, J.; Molenaar, J.; Wilde, B. De; Roberts, S. S.; Durinck, K.; Speleman, F.
RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition Journal Article
In: Science Advances, vol. 8, no. 28, pp. eabn1382, 2022.
@article{pmid35857500,
title = {RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition},
author = {C. Nunes and L. Depestel and L. Mus and K. M. Keller and L. Delhaye and A. Louwagie and M. Rishfi and A. Whale and N. Kara and S. R. Andrews and F. Dela Cruz and D. You and A. Siddiquee and C. T. Cologna and S. De Craemer and E. Dolman and C. Bartenhagen and F. De Vloed and E. Sanders and A. Eggermont and S. L. Bekaert and W. Van Loocke and J. W. Bek and G. Dewyn and S. Loontiens and G. Van Isterdael and B. Decaesteker and L. Tilleman and F. Van Nieuwerburgh and V. Vermeirssen and C. Van Neste and B. Ghesquiere and S. Goossens and S. Eyckerman and K. De Preter and M. Fischer and J. Houseley and J. Molenaar and B. De Wilde and S. S. Roberts and K. Durinck and F. Speleman},
url = {https://doi.org/10.1126/sciadv.abn1382},
year = {2022},
date = {2022-07-01},
urldate = {2022-07-01},
journal = {Science Advances},
volume = {8},
number = {28},
pages = {eabn1382},
abstract = {High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upon in vitro knockdown and accelerated tumor formation in a neuroblastoma zebrafish model coexpressing human RRM2 with MYCN. Forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition, while high RRM2 expression in human neuroblastomas correlates with high CHK1 activity. MYCN-driven zebrafish tumors with RRM2 co-overexpression exhibit differentially expressed DNA repair genes in keeping with enhanced ATR-CHK1 signaling activity. In vitro, RRM2 inhibition enhances intrinsic replication stress checkpoint addiction. Last, combinatorial RRM2-CHK1 inhibition acts synergistic in high-risk neuroblastoma cell lines and patient-derived xenograft models, illustrating the therapeutic potential.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upon in vitro knockdown and accelerated tumor formation in a neuroblastoma zebrafish model coexpressing human RRM2 with MYCN. Forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition, while high RRM2 expression in human neuroblastomas correlates with high CHK1 activity. MYCN-driven zebrafish tumors with RRM2 co-overexpression exhibit differentially expressed DNA repair genes in keeping with enhanced ATR-CHK1 signaling activity. In vitro, RRM2 inhibition enhances intrinsic replication stress checkpoint addiction. Last, combinatorial RRM2-CHK1 inhibition acts synergistic in high-risk neuroblastoma cell lines and patient-derived xenograft models, illustrating the therapeutic potential.
Goossens, S.; Cauwels, A.; Pieters, T.; Smedt, R. De; T'Sas, S.; Almeida, A.; Daneels, W.; Vlierberghe, P. Van; Tavernier, J.
Direct and indirect anti-leukemic properties of activity-on-target interferons for the treatment of T-cell acute lymphoblastic leukemia Journal Article
In: Haematologica, vol. 107, no. 6, pp. 1448–1453, 2022.
@article{pmid34647441,
title = {Direct and indirect anti-leukemic properties of activity-on-target interferons for the treatment of T-cell acute lymphoblastic leukemia},
author = {S. Goossens and A. Cauwels and T. Pieters and R. De Smedt and S. T'Sas and A. Almeida and W. Daneels and P. Van Vlierberghe and J. Tavernier},
url = {https://doi.org/10.3324/haematol.2021.278913},
year = {2022},
date = {2022-06-01},
urldate = {2022-06-01},
journal = {Haematologica},
volume = {107},
number = {6},
pages = {1448--1453},
abstract = {Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA; Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.
Pieters, T.; Almeida, A.; T'Sas, S.; Lemeire, K.; Hochepied, T.; Berx, G.; Kentsis, A.; Goossens, S.; Vlierberghe, P. Van
Myb drives B-cell neoplasms and myeloid malignancies in vivo Journal Article
In: Blood Advances, vol. 6, no. 10, pp. 2987–2991, 2022.
@article{pmid35020834,
title = {Myb drives B-cell neoplasms and myeloid malignancies in vivo },
author = {T. Pieters and A. Almeida and S. T'Sas and K. Lemeire and T. Hochepied and G. Berx and A. Kentsis and S. Goossens and P. Van Vlierberghe},
url = {https://doi.org/10.1182/bloodadvances.2021005955
},
year = {2022},
date = {2022-05-01},
urldate = {2022-05-01},
journal = {Blood Advances},
volume = {6},
number = {10},
pages = {2987--2991},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Trimpont, M. Van; Peeters, E.; Visser, Y. De; Schalk, A. M.; Mondelaers, V.; Moerloose, B. De; Lavie, A.; Lammens, T.; Goossens, S.; Vlierberghe, P. Van
Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy Journal Article
In: Cancers, vol. 14, no. 4, 2022.
@article{pmid35205650,
title = {Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy},
author = {M. Van Trimpont and E. Peeters and Y. De Visser and A. M. Schalk and V. Mondelaers and B. De Moerloose and A. Lavie and T. Lammens and S. Goossens and P. Van Vlierberghe},
url = {https://doi.org/10.3390/cancers14040902},
year = {2022},
date = {2022-02-01},
urldate = {2022-02-01},
journal = {Cancers},
volume = {14},
number = {4},
abstract = {L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.