ORCID Profile
0000-0001-9256-947X
Current Organisations
University of Lübeck
,
Princess Máxima Center
,
VU University Medical Center
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.C.6651055
Abstract: Abstract Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring i PIK3CA /i mutations showed increased sensitivity to ONC201, whereas those harboring i TP53 /i mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib. /
Publisher: American Society for Microbiology
Date: 02-2019
DOI: 10.1128/JVI.01173-18
Abstract: The two human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), can cause aggressive forms of cancer. These herpesviruses are strictly host specific, and therefore the homolog murine gammaherpesvirus 68 (MHV68) is a widely used model to obtain in vivo insights into the interaction between these two gammaherpesviruses and their host. Like EBV and KSHV, MHV68 establishes lifelong latency in B cells. The innate immune system serves as one of the first lines of host defense, with pattern recognition receptors such as the Toll-like receptors playing a crucial role in mounting a potent antiviral immune response to various pathogens. Here, we shed light on a yet unanticipated role of Toll-like receptor 7 in the recognition of MHV68 in a subset of immune cells called plasmacytoid dendritic cells, as well as on the control of this virus in its host.
Publisher: American Association for Cancer Research (AACR)
Date: 17-05-2023
DOI: 10.1158/0008-5472.22892044.V1
Abstract: All Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 17-05-2023
DOI: 10.1158/0008-5472.22892047.V1
Abstract: All Supplementary Figures and their captions.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.23683824
Abstract: All Supplementary Tables
Publisher: Springer Science and Business Media LLC
Date: 27-11-2019
DOI: 10.1007/S11060-018-03060-4
Abstract: There are two errors and one omission in the original article. Author Gottardo's correct name is Nicholas G. Gottardo, author Hulleman's correct affiliation is no. 3 (VUMC, Amsterdam), and the Acknowledgements should include the following sentence: "We would like to thank Dr Angel Montero Carcaboso (Hospital Sant Joan de Deu, Barcelona, Spain) for generously supplying the HSJD-DIPG007 cells."
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.23683827
Abstract: All Supplementary Figures and their captions.
Publisher: American Association for Cancer Research (AACR)
Date: 05-05-2023
DOI: 10.1158/0008-5472.CAN-23-0186
Abstract: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.
Publisher: American Association for Cancer Research (AACR)
Date: 17-05-2023
DOI: 10.1158/0008-5472.22892044
Abstract: All Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 17-05-2023
DOI: 10.1158/0008-5472.22892047
Abstract: All Supplementary Figures and their captions.
Publisher: Springer Science and Business Media LLC
Date: 27-01-2012
DOI: 10.1038/LEU.2011.388
Abstract: MLL-rearranged acute lymphoblastic leukemia (ALL) in infants is characterized by a poor clinical outcome and resistance to glucocorticoids (for ex le, prednisone and dexamethasone). As both the response to prednisolone in vitro and prednisone in vivo are predictive for clinical outcome, understanding and overcoming glucocorticoid resistance remains an essential step towards improving prognosis. Prednisolone-induced apoptosis depends on glucocorticoid-evoked Ca(2+) fluxes from the endoplasmic reticulum towards the mitochondria. Here, we demonstrate that in MLL-rearranged infant ALL, over-expression of S100A8 and S100A9 is associated with failure to induce free-cytosolic Ca(2+) and prednisolone resistance. Furthermore, we demonstrate that enforced expression of S100A8/S100A9 in prednisolone-sensitive MLL-rearranged ALL cells, rapidly leads to prednisolone resistance as a result of S100A8/S100A9 mediated suppression of prednisolone-induced free-cytosolic Ca(2+) levels. In addition, the Src kinase inhibitor PP2 markedly sensitized MLL-rearranged ALL cells otherwise resistant to prednisolone, via downregulation of S100A8 and S100A9, which allowed prednisolone-induced Ca(2+) fluxes to reach the mitochondria and trigger apoptosis. On the basis of this novel mechanism of prednisolone resistance, we propose that developing more specific S100A8/S100A9 inhibitors may well be beneficial for prednisolone-resistant MLL-rearranged infant ALL patients.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 07-2018
Abstract: Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age 3 or 10 years (11% v 3% and 33% v 23%, respectively P .001) and with longer symptom duration ( P .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively P = .008), ring enhancement (38% v 23%, respectively P = .007), necrosis (42% v 26%, respectively P = .009), and extrapontine extension (92% v 86%, respectively P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28 95% CI, 1.1 to 1.5 P = .002). We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.C.6651055.V2
Abstract: Abstract Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring i PIK3CA /i mutations showed increased sensitivity to ONC201, whereas those harboring i TP53 /i mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib. /
Publisher: American Association for Cancer Research (AACR)
Date: 17-05-2023
DOI: 10.1158/0008-5472.C.6651055.V1
Abstract: Abstract Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring i PIK3CA /i mutations showed increased sensitivity to ONC201, whereas those harboring i TP53 /i mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib. /
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.23683824.V1
Abstract: All Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/0008-5472.23683827.V1
Abstract: All Supplementary Figures and their captions.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2018
DOI: 10.1007/S11060-018-03038-2
Abstract: Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autopsy tumors to generate cultures and xenograft models. To further model development, we evaluated the collective international experience from 8 collaborating centers to develop DIPG pre-clinical models from patient-derived autopsies and biopsies. Univariate and multivariate analysis was performed to determine key factors associated with the success of in vitro and in vivo PDX development. In vitro cultures were successfully established from 57% of s les (84.2% of biopsies and 38.2% of autopsies). S les transferred in DMEM media were more likely to establish successful culture than those transported in Hibernate A. In vitro cultures were more successful from biopsies (84.2%) compared with autopsies (38.2%) and as monolayer on laminin-coated plates than as neurospheres. Primary cultures successfully established from autopsy s les were more likely to engraft in animal models than cultures established from biopsies (86.7% vs. 47.4%). Collectively, tumor engraftment was more successful when DIPG s les were directly implanted in mice (68%), rather than after culturing (40.7%). This multi-center study provides valuable information on the success rate of establishing patient-derived pre-clinical models of DIPG. The results can lead to further optimization of DIPG model development and ultimately assist in the investigation of new therapies for this aggressive pediatric brain tumor.
No related grants have been discovered for Esther Hulleman.