The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies
Abstract
:Simple Summary
Abstract
1. Introduction
2. Neurodevelopmental and Molecular Underpinnings of Medulloblastoma Subgroups
2.1. Cerebellar Embryonal Development
2.2. WNT-Activated Medulloblastoma
2.3. SHH-Activated Medulloblastoma
2.4. Group 3 Medulloblastoma
2.5. Group 4 Medulloblastoma
2.6. Intermediate Group 3/Group 4 Medulloblastoma
3. Subgroup-Specific Targeted Therapies in Medulloblastoma
3.1. WNT-Activated Medulloblastoma
3.2. SHH-Activated Medulloblastoma
3.3. Group 3 Medulloblastoma
3.4. Group 4 Medulloblastoma
4. Other Non-Specific Combination Therapies in Medulloblastoma
4.1. Targeting the PI3K/mTOR Pathway
4.2. Targeting Tyrosine Kinases
4.3. Targeting Vascular Endothelial Growth Factor
4.4. Immunotherapy
5. Conclusions and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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WNT-Activated | SHH-Activated | Group 3 | Group 4 | |
---|---|---|---|---|
Prevalence | 10% | 30% | 25% | 35% |
5-year survival | >90% | 70% | 50% | 75% |
Neurodevelopmental origin | Pontine mossy fibers of the lower rhombic lip | Granule neuron precursor cells of the upper rhombic lip | Unipolar brush cells and glutamatergic cerebellar nuclei of the upper rhombic lip | |
Commonly mutated genes | CTNNB1, DDX3X, CREBBP, SMARC4 | TP53, TERT, PTCH1, GLI2, SMO, SUFU | MYC, SOX11, PVT1, OTX2, GFI1/GFI1B | MYCN, SNCAIP, GFI1/GFI1B |
Important epigenetic players | ARID1, ARID2, SMARC4, promoter methylation of CDH1 | MLL2/KMT2D, MLL3/KMT2C, NCOR2, LDB1 | LSD1, PRC2, EZH2, BRD | KDM6A/UTX, LSD1 |
Group | Agent | Mechanism of Action | Trials | Type/Design | Population | Intervention | Status |
---|---|---|---|---|---|---|---|
SMO inhibitors | Sonidegib (LDE-225) | Binds to the transmembrane portion of the SMO protein and inhibits downstream signaling | NCT04402073 (PersoMed-I) | Phase II Comparative Randomized | Adult and post-pubertal patients with SHH-activated medulloblastoma | Sonidegib and reduced dose radiotherapy | Recruiting |
NCT01708174 | Phase II Single arm | Pediatric and adult patients with relapsed SHH-activated medulloblastoma | Sonidegib | Completed. Results available on ClinicalTrials.gov (accessed on 24 July 2023) | |||
NCT01208831 | Phase I Dose escalation | Adult patients with advanced solid tumors (including medulloblastoma) | Sonidegib | Completed. Results available on Novartis website | |||
NCT01125800 | Phase I/II Dose escalation | Pediatric and adult patients with recurrent or refractory SHH-activated medulloblastoma | Sonidegib | Completed. Results published [72] | |||
NCT00880308 | Phase I Dose escalation | Adult patients with advanced solid tumors (including medulloblastoma) | Sonidegib | Completed. Results published [167] | |||
Vismodegib (GDC-0449) | Binds to the transmembrane portion of the SMO protein and inhibits downstream signaling | NCT01878617 | Phase II Parallel assignment Non-randomized | Skeletally mature patients with newly diagnosed standard and high-risk SHH-activated medulloblastoma | Standard chemoradiotherapy with vesmodegib added to maintenance therapy | Active, not recruiting | |
NCT01601184 | Phase I/II Parallel assignment Randomized | Adult patients with recurrent or refractory SHH-activated medulloblastomas | Vismodegib plus temozolomide versus temozolomide alone | Terminated (number of successes not reached) | |||
NCT01208831 PBTC-032 | Phase II Single group | Pediatric patients with recurrent or refractory medulloblastoma without (stratum A) or with (Stratum B) SHH activation | Vismodegib | Completed. Published results [71] | |||
NCT00939484 PBTC-025B | Phase II Single group | Adult patients with recurrent or refractory medulloblastoma without (stratum A) or with (Stratum B) SHH activation | Vismodegib | Completed. Published results [71] | |||
NCT00822458 PBTC-025 | Phase I Dose finding | Young patients with recurrent or refractory medulloblastoma | Vismodegib | Completed. Published results [70] | |||
Taladegib (ENV-101) | Binds to the transmembrane portion of the SMO protein and inhibits downstream signaling | NCT05199584 | Phase II Parallel assignment Randomized | Adult patients with refractory advanced solid tumors (including medulloblastoma) with loss of function mutations in the PTCH1 gene | Taladegib | Recruiting | |
NCT01697514 | Phase I Single group | Pediatric patients with recurrent or refractory medulloblastoma or rhabdomyosarcoma | Taladegib | Withdrawn (poor recruitment) | |||
ZSP1602 | SMO antagonist (specific mechanism not known) | NCT03734913 | Phase I Parallel assignment Non-randomized | Adult patients with advanced solid tumors | ZSP1602 | Unknown (last update in July 2020 was recruiting) | |
LEQ506 | Second generation SMO antagonist (specific mechanism not known) [168] | NCT01106508 | Phase I Dose finding | Adult patients with advanced solid tumors | LEQ506 | Completed. Results available on Novartis website | |
GLI inhibitors | ATO | Direct inhibitor of GLI | NCT00024258 | Phase II Single group | Pediatric and adult patients with neuroblastoma and other pediatric solid tumors (nonmyeloid and nonlymphoid) | ATO | Completed. Results available on ClinicalTraial.gov (accessed on 24 July 2023) |
Silmitasertib (CX-4945) | CK2 antagonist that reduces the transcription of GLI genes | NCT03904862 | Phase I/II Parallel assignment Non-randomized | Skeletally immature (phase I) and skeletally mature (phase II) patients with recurrent SHH-activated medulloblastomas | Silmitasertib with or without surgical resection | Recruiting | |
HDAC inhibitors | Vorinostat | Inhibitor of class I and II HDACs | NCT01076530 | Phase I Single group | Young patients with relapsed or refractory primary CNS tumors | Vorinostat plus temozolomide | Completed. Published results [169] |
NCT00994500 | Phase I Single group | Young patients with refractory or recurrent solid tumors (including medulloblastoma) | Vorinostat and Bortezomib (ubiquitin-proteosome pathway inhibitor) | Completed. Published results [170] | |||
NCT00867178 | Phase I Single group | Younger patients with newly diagnosed CNS embryonal tumors | Adding vorinostat and isotretinoin to induction chemotherapy (cisplatin, etoposide, vincristine, cyclophosphamide) | Completed. Published results [171] | |||
NCT00217412 | Phase I Parallel assignment Non-randomized | Young patients with recurrent or refractory solid tumors (including medulloblastoma), lymphoma, or leukemia | Vorinostat plus isotretinoin | Completed. Published results [172] | |||
Panobinostat (MTX110) | Pan-HDAC inhibitor | NCT04315064 | Phase I Single group | Pediatric and adult patients with recurrent medulloblastoma | Infusions of Panobinostat into the fourth ventricle of the brain or tumor resection cavity | Recruiting | |
Fimepinostat | Pan-HDAC and PI3K inhibitor | NCT03893487 PNOC016 | Phase I Single group | Pediatric and adult patients with newly diagnosed DIPG, recurrent medulloblastoma (any subtype), or recurrent high-grade glioma | Fimepinostat 2 days preoperatively followed by surgical resection, then maintenance with fimepinostat | Active, not recruiting | |
Romidepsin (FR901228) | HDAC inhibitor | NCT00053963 | Phase I Single group | Pediatric patients with refractory or recurrent solid tumors | Romidepsin | Completed. Results not available | |
Cell cycle-disrupting agents | Prexasertib (LY2606368) | Checkpoint kinases 1 and 2 (CHK1/2) inhibitor | NCT04023669 (St. Jude ELIOT) | Phase I Parallel assignment Non-randomized | Pediatric and adult (up to 24 years old) patients with refractory or recurrent SHH-activated, group 3, or group 4 medulloblastoma | Prexasertib in combination with cyclophosphamide (all three subtypes) or gemcitabine (only groups 3 and 4) | Active, not recruiting |
Palbociclib | CDK4/6 inhibitor | NCT03709680 | Phase I-Dose escalation Phase II-Randomized | Pediatric patients with refractory or recurrent solid tumors (including medulloblastoma) | Palboociclib combined with chemotherapy (temozolomide plus irinotecan or topotecan plus cyclophosphamide) | Recruiting | |
NCT03526250 (Subprotocol of the NCI-COG Pediatric MATCH trial) | Phase II Single group | Pediatric patients with relapsed or refractory Rb-positive solid tumors non-Hodgkin lymphoma, or histiocytic disorders with activating alterations in cell cycle genes | Palbociclib | Active, not recruiting | |||
NCT02255461 (PBTC-042) | Phase I Single group | Pediatric patients with Rb-positive recurrent, progressive, or refractory primary CNS tumors. | Palbociclib | Completed. Published results [108] | |||
Ribociclib (LEE011) | CDK4/6 inhibitor | NCT05429502 | Phase I/II Parallel assignment Randomized | Pediatric patients with relapsed or refractory solid tumors | Ribociclib combined with topotecan and temozolomide | Recruiting | |
NCT03434262 (SJDAWN) | Phase I Parallel assignment Non-randomized | Pediatric and adult patients with refractory or recurrent brain tumors | Stratum A: ribociclib and gemcitabine for patients with recurrent/refractory group 3/4 medulloblastoma or ependymoma Stratum B: ribociclib and trametinib for recurrent/refractory WNT-activated or SHH-activated medulloblastoma and other CNS tumors Stratum C: ribociclib and sonidegib for skeletally mature patients with recurrent/refractory SHH-activated medulloblastoma | Active, not recruiting | |||
NCT03387020 | Phase I Single group | Pediatric patients with recurrent, progressive, or refractory CNS tumors | Ribociclib and everolimus (mTOR inhibitor) | Completed. Published results [173] | |||
Abemaciclib | CDK4/6 inhibitor | NCT04238819 | Phase I Dose escalation | Pediatric patients with recurrent or refractory solid tumors | Abemaciclib combined with temozolomide alone or with irinotecan and temozolomide | Recruiting | |
Tyrosine kinase inhibitors (TKIs) | Apatinib | TKI that blocks the activity of vascular endothelial growth factor receptor 2 (VEGFR2) | NCT04501718 | Phase II Single group | Pediatric patients with recurrent medulloblastoma | Apatinib combined with temozolomide and etoposide | Recruiting |
Volitinib | TKI that blocks cMET signaling | NCT03598244 | Phase I Single group | Pediatric patients with refractory, progressive, or recurrent primary CNS tumors | Volitinib | Recruiting | |
Erdafitinib | TKI that blocks fibroblast growth factor receptor | NCT03210714 (Subprotocol of the NCI-COG Pediatric MATCH trial) | Phase II Single group | Pediatric patients with relapsed or refractory solid tumors non-Hodgkin lymphoma, or histiocytic disorders with FGFR mutations | Erdafitinib | Active, not recruiting | |
Entrectinib (Rxdx-101) | TKI that blocks the activity of tropomyosin receptor kinases, ROS1, and ALK | NCT02650401 | Phase I/II Single group | Pediatric patients with locally advanced, metastatic, or refractory solid or primary CNS tumors | Entrectinib | Active, not recruiting | |
Adavosertib (MK-1775) | TKI that block the activity of WEE1 | NCT02095132 | Phase I/II Single group | Pediatric patients with relapsed or refractory solid tumors | Adavosertib combined with irinotecan | Active, not recruiting | |
Cediranib (AZD-2171) | TKI that blocks the activity of VEGF | NCT00326664 | Phase I Single group | Pediatric patients with recurrent, progressive, or refractory primary CNS tumors | Cediranib | Completed. Published results [174] | |
Lapatinib | Dual TKI that blocks epidermal growth factor receptor and HER2 signaling | NCT00095940 | Phase I/II Single group | Pediatric patients with recurrent or refractory CNS tumors | Lapatinib | Completed. Results available on ClinicalTrials.gov (accessed on 24 July 2023) | |
Antiangiogenic factors | Pomalidomide | Decreases the concentrations of VEGF and HIF1α. Increases the production of immune-stimulatory cytokines | NCT03257631 | Phase II Single group | Pediatric patients with recurrent or progressive primary brain tumors | Pomalidomide | Completed. Published results [175] |
Bevacizumab and other drugs (multidrug) | Bevacizumab is a monoclonal antibody that binds VEGF. Thalidomide, celecoxib, and fenofibrate also have antiangiogenic effects [176] | NCT01356290 | Phase II Single group | Pediatric patients with recurrent or progressive medulloblastoma, ependymoma, or ATRT. | Bevacizumab in combination with 5 oral drugs (thalidomide, celecoxib, fenofibrate, etoposide, and cyclophosphamide) | Recruiting | |
PTC-299 | Targets VEGF mRNA and inhibits their translation | NCT01158300 | Phase I Single group | Pediatric patients with recurrent or refractory primary CNS tumors | PTC-299 | Completed. Published results [177] | |
Cilengitide | Integrin antagonist that disrupts endothelial interactions | NCT00063973 PBTC-012 | Phase I Single group | Pediatric patients with refractory primary brain tumors | Cilengitide | Completed. Published results [178] | |
Immunomodulatory agents | Nivolumab | Monoclonal antibody against the immune checkpoint protein programmed death 1 (PD1) | NCT03585465 | Phase I/II Parallel assignment Randomized | Pediatric patients with relapsed or refractory solid tumors | Nivolumab combined with cyclophosphamide and vinblastine (Arm A), capecitabine (Arm B), or metronomic chemotherapy (Metronomic+ Nivolumab arm) | Recruiting |
NCT03173950 | Phase II Parallel assignment Non-randomized | Adult patients with recurrent select rare CNS cancers (including medulloblastoma) | Nivolumab | Recruiting | |||
Pembrolizamab | Monoclonal antibody against the immune checkpoint protein PD1 | NCT02359565 | Phase I Single group | Pediatric patients with recurrent, progressive, or refractory high-grade gliomas, DIPGs, hypermutated brain tumors, ependymoma, or medulloblastoma | Pembrolizumab | Recruiting | |
Cemiplimab (REGN2810) | Monoclonal antibody against the immune checkpoint protein PD1 | NCT03690869 | Phase I | Pediatric patients with relapsed or refractory solid or CNS tumors | Cemiplimab | Recruiting | |
Indoximod | Inhibitor of the immune-suppressive enzyme Indoleamine-2,3-dioxygenase (IDO) | NCT05106296 | Phase I Single group | Patients aged 12–25 years with pediatric brain tumors | Indoximod combined with ibrutinib (Bruton’s tyrosine kisase inhibitor, and chemoradiotherapy | Recruiting | |
NCT04049669 | Phase II Crossover Non-randomized | Pediatric patients with relapsed brain tumors or newly diagnosed DIPG | Indoximod administered during chemotherapy and/or radiation therapy | Recruiting | |||
NCT02502708 | Phase I Parallel assignment Non-randomized | Pediatric patients with progressive primary brain tumors | Indoximod in combination with temozolomide-based chemotherapy | Completed. No results available | |||
Sotigalimab (APX005M) | CD40 agonist that activates antigen-presenting cells | NCT03389802 | Phase I Sequential Non-randomized | Pediatric patients with recurrent, progressive, or refractory primary malignant CNS tumor | Sotigalimab | Active, not recruiting | |
EZH2 inhibitors | Tazemostat | EZH2 inhibitor | NCT03213665 (Subprotocol of the NCI-COG Pediatric MATCH trial) | Phase II Single group | Pediatric patients with relapsed or refractory solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with gain of function mutations in EZH2 or loss of function mutations in SMARCB1 or SMARCA4 | Tazemostat | Active, not recruiting |
PI3K/mTOR inhibitors | Samotolisib (LY3023414) | Dual PI3K and mTOR inhibitor | NCT03213678 (Subprotocol of the NCI-COG Pediatric MATCH trial) | Phase II Single group | Pediatric patients with relapsed or refractory solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with TSC loss of function mutations, and/or other PI3K/mTOR activating mutations | Samotolisib | Recruiting |
Sirolimus | mTOR inhibitor | NCT02574728 | Phase II Single group | Pediatric patients with relapsed or refractory solid or CNS tumors | Sirolimus in combination with metronomic chemotherapy | Recruiting | |
BRD inhibitors | BMS-986158 and BMS-986378 | BRD inhibitors that prevent the interaction between BET proteins and histones | NCT03936465 | Phase I Parallel assignment Non-randomized | Pediatric patients with relapsed or progressive solid or CNS tumors | BMS-986158 or BMS-986378 as monotherapies | Recruiting |
Gamma secretase inhibitors | RO492909 7 | Blocks the cleavage of Notch intracellular domain (NICD) and its translocation to the nucleus to induce the expression of Notch pathway effector genes | NCT01088763 | Phase I/II Single group | Pediatric patients with relapsed or refractory solid tumors, CNS tumors, lymphoma, or T-cell leukemia | RO4929097 | Terminated |
MK0752 | Blocks the cleavage of Notch intracellular domain (NICD) and its translocation to the nucleus to induce the expression of Notch pathway effector genes | NCT00572182 | Phase I Single group | Pediatric patients with recurrent or refractory CNS tumors | MK0752 | Terminated due to discontinued financial support | |
JAK/STAT inhibitors | WP1066 | JAK2/STAT3 pathway inhibitor | NCT04334863 | Phase I Single group | Pediatric patients with recurrent or progressive malignant brain tumors | WP1066 | Completed. No results available |
Others | TB-403 | Monoclonal antibody against placental growth factor (PIGF) | NCT02748135 | Phase I Single group | Pediatric patients with relapsed or refractory medulloblastoma, neuroblastoma, Ewing sarcoma, and alveolar rhabdomyosarcoma | TB-403 | Completed. Published results [179] |
Mebendazole | Antiparasitic drug that has been shown to have anti-proliferative and proapoptotic roles in several cancer types via its ability to modulate several oncogenic pathways (including SHH, MEK/ERK, and STAT1/2) | NCT02644291 | Phase I Single group | Pediatric patients with recurrent or progressive brain tumors | Mebendazole | Completed. No results available |
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Slika, H.; Alimonti, P.; Raj, D.; Caraway, C.; Alomari, S.; Jackson, E.M.; Tyler, B. The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies. Cancers 2023, 15, 3889. https://doi.org/10.3390/cancers15153889
Slika H, Alimonti P, Raj D, Caraway C, Alomari S, Jackson EM, Tyler B. The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies. Cancers. 2023; 15(15):3889. https://doi.org/10.3390/cancers15153889
Chicago/Turabian StyleSlika, Hasan, Paolo Alimonti, Divyaansh Raj, Chad Caraway, Safwan Alomari, Eric M. Jackson, and Betty Tyler. 2023. "The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies" Cancers 15, no. 15: 3889. https://doi.org/10.3390/cancers15153889