Publications
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.
Jonckheere, S.; Adams, J.; Groote, D. De; Campbell, K.; Berx, G.; Goossens, S.
Epithelial-Mesenchymal Transition (EMT) as a Therapeutic Target Journal Article
In: Cells Tissues Organs, vol. 211, no. 2, pp. 157–182, 2022.
@article{pmid33401271,
title = {Epithelial-Mesenchymal Transition (EMT) as a Therapeutic Target},
author = {S. Jonckheere and J. Adams and D. De Groote and K. Campbell and G. Berx and S. Goossens},
url = {https://doi.org/10.1159/000512218},
year = {2022},
date = {2022-01-01},
urldate = {2022-01-01},
journal = {Cells Tissues Organs},
volume = {211},
number = {2},
pages = {157--182},
abstract = {Metastasis is the spread of cancer cells from the primary tumour to distant sites and organs throughout the body. It is the primary cause of cancer morbidity and mortality, and is estimated to account for 90% of cancer-related deaths. During the initial steps of the metastatic cascade, epithelial cancer cells undergo an epithelial-mesenchymal transition (EMT), and as a result become migratory and invasive mesenchymal-like cells while acquiring cancer stem cell properties and therapy resistance. As EMT is involved in such a broad range of processes associated with malignant transformation, it has become an increasingly interesting target for the development of novel therapeutic strategies. Anti-EMT therapeutic strategies could potentially not only prevent the invasion and dissemination of cancer cells, and as such prevent the formation of metastatic lesions, but also attenuate cancer stemness and increase the effectiveness of more classical chemotherapeutics. In this review, we give an overview about the pros and cons of therapies targeting EMT and discuss some already existing candidate drug targets and high-throughput screening tools to identify novel anti-EMT compounds.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Metastasis is the spread of cancer cells from the primary tumour to distant sites and organs throughout the body. It is the primary cause of cancer morbidity and mortality, and is estimated to account for 90% of cancer-related deaths. During the initial steps of the metastatic cascade, epithelial cancer cells undergo an epithelial-mesenchymal transition (EMT), and as a result become migratory and invasive mesenchymal-like cells while acquiring cancer stem cell properties and therapy resistance. As EMT is involved in such a broad range of processes associated with malignant transformation, it has become an increasingly interesting target for the development of novel therapeutic strategies. Anti-EMT therapeutic strategies could potentially not only prevent the invasion and dissemination of cancer cells, and as such prevent the formation of metastatic lesions, but also attenuate cancer stemness and increase the effectiveness of more classical chemotherapeutics. In this review, we give an overview about the pros and cons of therapies targeting EMT and discuss some already existing candidate drug targets and high-throughput screening tools to identify novel anti-EMT compounds.
Loret, N.; Vandamme, N.; Coninck, J. De; Taminau, J.; Clercq, K. De; Blancke, G.; Jonckheere, S.; Goossens, S.; Lemeire, K.; Prijck, S. De; Verstaen, K.; Seurinck, R.; Dorpe, J. Van; Weyers, S.; Denys, H.; de Vijver, K. Van; Lambrecht, B. N.; Tummers, P.; Saeys, Y.; Berx, G.
In: Molecular Cancer Research, vol. 20, no. 10, pp. 1532–1547, 2022.
@article{pmid35749080,
title = {Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer},
author = {N. Loret and N. Vandamme and J. De Coninck and J. Taminau and K. De Clercq and G. Blancke and S. Jonckheere and S. Goossens and K. Lemeire and S. De Prijck and K. Verstaen and R. Seurinck and J. Van Dorpe and S. Weyers and H. Denys and K. Van de Vijver and B. N. Lambrecht and P. Tummers and Y. Saeys and G. Berx},
url = {https://doi.org/10.1158/1541-7786.mcr-21-0565},
year = {2022},
date = {2022-00-01},
urldate = {2022-00-01},
journal = {Molecular Cancer Research},
volume = {20},
number = {10},
pages = {1532--1547},
abstract = {High-grade serous ovarian cancer (HGSOC) is responsible for the largest number of ovarian cancer deaths. The frequent therapy-resistant relapses necessitate a better understanding of mechanisms driving therapy resistance. Therefore, we mapped more than a hundred thousand cells of HGSOC patients in different phases of the disease, using single-cell RNA sequencing. Within patients, we compared chemonaive with chemotreated samples. As such, we were able to create a single-cell atlas of different HGSOC lesions and their treatment. This revealed a high intrapatient concordance between spatially distinct metastases. In addition, we found remarkable baseline differences in transcriptomics of ascitic and solid cancer cells, resulting in a different response to chemotherapy. Moreover, we discovered different robust subtypes of cancer-associated fibroblasts (CAF) in all patients. Besides inflammatory CAFs, vascular CAFs, and matrix CAFs, we identified a new CAF subtype that was characterized by high expression of STAR, TSPAN8, and ALDH1A1 and clearly enriched after chemotherapy. Together, tumor heterogeneity in both cancer and stromal cells contributes to therapy resistance in HGSOC and could form the basis of novel therapeutic strategies that differentiate between ascitic and solid disease. The newly characterized differences between ascitic and solid cancer cells before and after chemotherapy could inform novel treatment strategies for metastatic HGSOC.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
High-grade serous ovarian cancer (HGSOC) is responsible for the largest number of ovarian cancer deaths. The frequent therapy-resistant relapses necessitate a better understanding of mechanisms driving therapy resistance. Therefore, we mapped more than a hundred thousand cells of HGSOC patients in different phases of the disease, using single-cell RNA sequencing. Within patients, we compared chemonaive with chemotreated samples. As such, we were able to create a single-cell atlas of different HGSOC lesions and their treatment. This revealed a high intrapatient concordance between spatially distinct metastases. In addition, we found remarkable baseline differences in transcriptomics of ascitic and solid cancer cells, resulting in a different response to chemotherapy. Moreover, we discovered different robust subtypes of cancer-associated fibroblasts (CAF) in all patients. Besides inflammatory CAFs, vascular CAFs, and matrix CAFs, we identified a new CAF subtype that was characterized by high expression of STAR, TSPAN8, and ALDH1A1 and clearly enriched after chemotherapy. Together, tumor heterogeneity in both cancer and stromal cells contributes to therapy resistance in HGSOC and could form the basis of novel therapeutic strategies that differentiate between ascitic and solid disease. The newly characterized differences between ascitic and solid cancer cells before and after chemotherapy could inform novel treatment strategies for metastatic HGSOC.
2021
Pieters, T.; T'Sas, S.; Vanhee, S.; Almeida, A.; Driege, Y.; Roels, J.; Loocke, W. Van; Daneels, W.; Baens, M.; Marchand, A.; Trimpont, M. Van; Matthijssens, F.; Morscio, J.; Lemeire, K.; Lintermans, B.; Reunes, L.; Chaltin, P.; Offner, F.; Dorpe, J. Van; Hochepied, T.; Berx, G.; Beyaert, R.; Staal, J.; Vlierberghe, P. Van; Goossens, S.
Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice Journal Article
In: Journal of Experimental Medicine, vol. 218, no. 10, 2021.
@article{pmid34406363,
title = {Cyclin D2 overexpression drives B1a-derived MCL-like lymphoma in mice},
author = {T. Pieters and S. T'Sas and S. Vanhee and A. Almeida and Y. Driege and J. Roels and W. Van Loocke and W. Daneels and M. Baens and A. Marchand and M. Van Trimpont and F. Matthijssens and J. Morscio and K. Lemeire and B. Lintermans and L. Reunes and P. Chaltin and F. Offner and J. Van Dorpe and T. Hochepied and G. Berx and R. Beyaert and J. Staal and P. Van Vlierberghe and S. Goossens},
url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377631/pdf/JEM_20202280.pdf},
year = {2021},
date = {2021-10-04},
urldate = {2021-10-04},
journal = {Journal of Experimental Medicine},
volume = {218},
number = {10},
abstract = {Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with poor long-term overall survival. Currently, MCL research and development of potential cures is hampered by the lack of good in vivo models. MCL is characterized by recurrent translocations of CCND1 or CCND2, resulting in overexpression of the cell cycle regulators cyclin D1 or D2, respectively. Here, we show, for the first time, that hematopoiesis-specific activation of cyclin D2 is sufficient to drive murine MCL-like lymphoma development. Furthermore, we demonstrate that cyclin D2 overexpression can synergize with loss of p53 to form aggressive and transplantable MCL-like lymphomas. Strikingly, cyclin D2-driven lymphomas display transcriptional, immunophenotypic, and functional similarities with B1a B cells. These MCL-like lymphomas have B1a-specific B cell receptors (BCRs), show elevated BCR and NF-κB pathway activation, and display increased MALT1 protease activity. Finally, we provide preclinical evidence that inhibition of MALT1 protease activity, which is essential for the development of early life-derived B1a cells, can be an effective therapeutic strategy to treat MCL. },
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with poor long-term overall survival. Currently, MCL research and development of potential cures is hampered by the lack of good in vivo models. MCL is characterized by recurrent translocations of CCND1 or CCND2, resulting in overexpression of the cell cycle regulators cyclin D1 or D2, respectively. Here, we show, for the first time, that hematopoiesis-specific activation of cyclin D2 is sufficient to drive murine MCL-like lymphoma development. Furthermore, we demonstrate that cyclin D2 overexpression can synergize with loss of p53 to form aggressive and transplantable MCL-like lymphomas. Strikingly, cyclin D2-driven lymphomas display transcriptional, immunophenotypic, and functional similarities with B1a B cells. These MCL-like lymphomas have B1a-specific B cell receptors (BCRs), show elevated BCR and NF-κB pathway activation, and display increased MALT1 protease activity. Finally, we provide preclinical evidence that inhibition of MALT1 protease activity, which is essential for the development of early life-derived B1a cells, can be an effective therapeutic strategy to treat MCL.