Cancers

Editorial

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3 pages, 185 KiB

Open AccessEditorial

Special Issue: Childhood Brain Cancer Treatment

by Stefano Mastrangelo

Cancers 2023, 15(21), 5278; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15215278 - 3 Nov 2023

Viewed by 504

Abstract

Brain cancer is the second most common childhood malignancy and is the leading cause of death among all pediatric cancers [...] Full article

(This article belongs to the Special Issue Childhood Brain Cancer Treatment)

Research

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20 pages, 4847 KiB

Open AccessArticle

STAT3 Inhibition Attenuates MYC Expression by Modulating Co-Activator Recruitment and Suppresses Medulloblastoma Tumor Growth by Augmenting Cisplatin Efficacy In Vivo

by Kyle A. Rohrer, Heyu Song, Anum Akbar, Yingling Chen, Suravi Pramanik, Phillip J. Wilder, Erin M. McIntyre, Nagendra K. Chaturvedi, Kishor K. Bhakat, Angie Rizzino, Don W. Coulter and Sutapa Ray

Cancers 2023, 15(8), 2239; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15082239 - 11 Apr 2023

Cited by 1 | Viewed by 2074

Abstract

MB is a common childhood malignancy of the central nervous system, with significant morbidity and mortality. Among the four molecular subgroups, MYC-amplified Group 3 MB is the most aggressive type and has the worst prognosis due to therapy resistance. The present study aimed [...] Read more.

MB is a common childhood malignancy of the central nervous system, with significant morbidity and mortality. Among the four molecular subgroups, MYC-amplified Group 3 MB is the most aggressive type and has the worst prognosis due to therapy resistance. The present study aimed to investigate the role of activated STAT3 in promoting MB pathogenesis and chemoresistance via inducing the cancer hallmark MYC oncogene. Targeting STAT3 function either by inducible genetic knockdown (KD) or with a clinically relevant small molecule inhibitor reduced tumorigenic attributes in MB cells, including survival, proliferation, anti-apoptosis, migration, stemness and expression of MYC and its targets. STAT3 inhibition attenuates MYC expression by affecting recruitment of histone acetyltransferase p300, thereby reducing enrichment of H3K27 acetylation in the MYC promoter. Concomitantly, it also decreases the occupancy of the bromodomain containing protein-4 (BRD4) and phosphoSer2-RNA Pol II (pSer2-RNAPol II) on MYC, resulting in reduced transcription. Importantly, inhibition of STAT3 signaling significantly attenuated MB tumor growth in subcutaneous and intracranial orthotopic xenografts, increased the sensitivity of MB tumors to cisplatin, and improved the survival of mice bearing high-risk MYC-amplified tumors. Together, the results of our study demonstrate that targeting STAT3 may be a promising adjuvant therapy and chemo-sensitizer to augment treatment efficacy, reduce therapy-related toxicity and improve quality of life in high-risk pediatric patients. Full article

(This article belongs to the Special Issue Childhood Brain Cancer Treatment)

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14 pages, 2565 KiB

Open AccessArticle

Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma

by Ricarda Wickert, Thomas Tessonnier, Maximilian Deng, Sebastian Adeberg, Katharina Seidensaal, Line Hoeltgen, Jürgen Debus, Klaus Herfarth and Semi B. Harrabi

Cancers 2022, 14(23), 5865; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235865 - 28 Nov 2022

Cited by 1 | Viewed by 1636

Abstract

Ependymomas are the third most-frequent pediatric brain tumors. To prevent local recurrence, the resection site should be irradiated. Compared to photon radiation treatment, proton therapy often achieves even better results regarding target coverage and organ-sparing. Due to their physical properties, helium ions could [...] Read more.

Ependymomas are the third most-frequent pediatric brain tumors. To prevent local recurrence, the resection site should be irradiated. Compared to photon radiation treatment, proton therapy often achieves even better results regarding target coverage and organ-sparing. Due to their physical properties, helium ions could further reduce side effects, providing better protection of healthy tissue despite similar target coverage. In our in silico study, 15 pediatric ependymoma patients were considered. All patients underwent adjuvant radiotherapeutic treatment with active-scanned protons at Heidelberg Ion Beam Therapy Center (HIT). Both helium ion and highly conformal IMRT plans were calculated to evaluate the potential dosimetric advantage of ion beam therapy compared to the current state-of-the-art photon-based treatments. To estimate the potential clinical benefit of helium ions, normal tissue complication probabilities (NTCP) were calculated. Target coverage was comparable in all three modalities. As expected, the integral dose absorbed by healthy brain tissue could be significantly reduced with protons by up to −48% vs. IMRT. Even compared to actively scanned protons, relative dose reductions for critical neuronal structures of up to another −39% were achieved when using helium ions. The dose distribution of helium ions is significantly superior when compared to proton therapy and IMRT due to the improved sparing of OAR. In fact, previous studies could clearly demonstrate that the dosimetric advantage of protons translates into a measurable clinical benefit for pediatric patients with brain tumors. Given the dose–response relationship of critical organs at risk combined with NTCP calculation, the results of our study provide a strong rationale that the use of helium ions has the potential to even further reduce the risk for treatment related sequelae. Full article

(This article belongs to the Special Issue Childhood Brain Cancer Treatment)

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17 pages, 1408 KiB

Open AccessArticle

H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines

by Andria Rakotomalala, Quentin Bailleul, Clara Savary, Mélanie Arcicasa, Maud Hamadou, Paul Huchedé, Audrey Hochart, Audrey Restouin, Remy Castellano, Yves Collette, Emma Dieny, Audrey Vincent, Pierre-Olivier Angrand, Xuefen Le Bourhis, Pierre Leblond, Alessandro Furlan, Marie Castets, Eddy Pasquier and Samuel Meignan

Cancers 2021, 13(21), 5551; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215551 - 5 Nov 2021

Cited by 8 | Viewed by 3722

Abstract

High-grade gliomas represent the most lethal class of pediatric tumors, and their resistance to both radio- and chemotherapy is associated with a poor prognosis. Recurrent mutations affecting histone genes drive the tumorigenesis of some pediatric high-grade gliomas, and H3K27M mutations are notably characteristic [...] Read more.

High-grade gliomas represent the most lethal class of pediatric tumors, and their resistance to both radio- and chemotherapy is associated with a poor prognosis. Recurrent mutations affecting histone genes drive the tumorigenesis of some pediatric high-grade gliomas, and H3K27M mutations are notably characteristic of a subtype of gliomas called DMG (Diffuse Midline Gliomas). This dominant negative mutation impairs H3K27 trimethylation, leading to profound epigenetic modifications of genes expression. Even though this mutation was described as a driver event in tumorigenesis, its role in tumor cell resistance to treatments has not been deciphered so far. To tackle this issue, we expressed the H3.3K27M mutated histone in three initially H3K27-unmutated pediatric glioma cell lines, Res259, SF188, and KNS42. First, we validated these new H3.3K27M-expressing models at the molecular level and showed that K27M expression is associated with pleiotropic effects on the transcriptomic signature, largely dependent on cell context. We observed that the mutation triggered an increase in cell growth in Res259 and SF188 cells, associated with higher clonogenic capacities. Interestingly, we evidenced that the mutation confers an increased resistance to ionizing radiations in Res259 and KNS42 cells. Moreover, we showed that H3.3K27M mutation impacts the sensitivity of Res259 cells to specific drugs among a library of 80 anticancerous compounds. Altogether, these data highlight that, beyond its tumorigenic role, H3.3K27M mutation is strongly involved in pediatric glioma cells’ resistance to therapies, likely through transcriptomic reprogramming. Full article

(This article belongs to the Special Issue Childhood Brain Cancer Treatment)

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16 pages, 898 KiB

Open AccessArticle

Neurocognitive Outcomes in Pediatric Patients Following Brain Irradiation

by Katharina Weusthof, Peggy Lüttich, Sebastian Regnery, Laila König, Denise Bernhardt, Olaf Witt, Klaus Herfarth, Andreas Unterberg, Christine Jungk, Benjamin Farnia, Stephanie E. Combs, Jürgen Debus, Stefan Rieken, Semi Harrabi and Sebastian Adeberg

Cancers 2021, 13(14), 3538; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143538 - 15 Jul 2021

Cited by 14 | Viewed by 2260

Abstract

Advanced radiation techniques can reduce the severity of neurocognitive sequelae in young brain tumor patients. In the present analysis, we sought to compare neurocognitive outcomes after proton irradiation with patients who underwent photon radiotherapy (RT) and surgery. Neurocognitive outcomes were evaluated in 103 [...] Read more.

Advanced radiation techniques can reduce the severity of neurocognitive sequelae in young brain tumor patients. In the present analysis, we sought to compare neurocognitive outcomes after proton irradiation with patients who underwent photon radiotherapy (RT) and surgery. Neurocognitive outcomes were evaluated in 103 pediatric brain tumor patients (proton RT n = 26, photon RT n = 30, surgery n = 47) before and after treatment. Comparison of neurocognitive outcomes following different treatment modalities were analyzed over four years after treatment completion. Longitudinal analyses included 42 months of follow-up after proton RT and 55 months after photon RT and surgery. Neurocognitive assessment included standardized tests examining seven domains. A comparison of neurocognitive outcomes after RT (proton and photon with >90% additional surgery) and surgery showed no significant differences in any neurocognitive domain. Neurocognitive functioning tests after proton RT failed to identify alterations compared to baseline testing. Long-term follow up over four years after photon RT showed a decrease in non-verbal intelligence (−9.6%; p = 0.01) and visuospatial construction (−14.9%; p = 0.02). After surgery, there was a decline in non-verbal intelligence (−10.7%; p = 0.01) and processing speed (14.9%; p = 0.002). Differences in neurocognitive outcomes between RT and surgical cohorts in direct intermodal comparison at long-term follow-up were not identified in our study, suggesting that modern radiation therapy does not affect cognition as much as in the past. There were no alterations in long-term neurocognitive abilities after proton RT, whereas decline of processing speed, non-verbal intelligence, and visuospatial abilities were observed after both photon RT and surgery. Domains dependent on intact white matter structures appear particularly vulnerable to brain tumor treatment irrespective of treatment approach. Full article

(This article belongs to the Special Issue Childhood Brain Cancer Treatment)

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Review

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18 pages, 666 KiB

Open AccessReview

BRAF and MEK Targeted Therapies in Pediatric Central Nervous System Tumors

by Dario Talloa, Silvia Triarico, Pierpaolo Agresti, Stefano Mastrangelo, Giorgio Attinà, Alberto Romano, Palma Maurizi and Antonio Ruggiero

Cancers 2022, 14(17), 4264; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174264 - 31 Aug 2022

Cited by 7 | Viewed by 2829

Abstract

BRAF is a component of the MAPK and PI3K/AKT/mTOR pathways that play a crucial role in cellular proliferation, differentiation, migration, and angiogenesis. Pediatric central nervous system tumors very often show mutations of the MAPK pathway, as demonstrated by next-generation sequencing (NGS), which now [...] Read more.

BRAF is a component of the MAPK and PI3K/AKT/mTOR pathways that play a crucial role in cellular proliferation, differentiation, migration, and angiogenesis. Pediatric central nervous system tumors very often show mutations of the MAPK pathway, as demonstrated by next-generation sequencing (NGS), which now has an increasing role in cancer diagnostics. The MAPK mutated pathway in pediatric CNS tumors is the target of numerous drugs, approved or under investigation in ongoing clinical trials. In this review, we describe the main aspects of MAPK and PI3K/AKT/mTOR signaling pathways, with a focus on the alterations commonly involved in tumorigenesis. Furthermore, we reported the main available data about current BRAF and MEK targeted therapies used in pediatric low-grade gliomas (pLLGs), pediatric high-grade gliomas (pHGGs), and other CNS tumors that often present BRAF or MEK mutations. Further molecular stratification and clinical trial design are required for the treatment of pediatric CNS tumors with BRAF and MEK inhibitors. Full article

(This article belongs to the Special Issue Childhood Brain Cancer Treatment)

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15 pages, 1123 KiB

Open AccessReview

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of Pediatric Medulloblastoma

by Francia Y. Fang, Jared S. Rosenblum, Winson S. Ho and John D. Heiss

Cancers 2022, 14(9), 2285; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092285 - 3 May 2022

Cited by 16 | Viewed by 6813

Abstract

Pediatric medulloblastoma (MB) is the most common pediatric brain tumor with varying prognoses depending on the distinct molecular subtype. The four consensus subgroups are WNT, Sonic hedgehog (SHH), Group 3, and Group 4, which underpin the current 2021 WHO classification of MB. While [...] Read more.

Pediatric medulloblastoma (MB) is the most common pediatric brain tumor with varying prognoses depending on the distinct molecular subtype. The four consensus subgroups are WNT, Sonic hedgehog (SHH), Group 3, and Group 4, which underpin the current 2021 WHO classification of MB. While the field of knowledge for treating this disease has significantly advanced over the past decade, a deeper understanding is still required to improve the clinical outcomes for pediatric patients, who are often vulnerable in ways that adult patients are not. Here, we discuss how recent insights into the pathogenesis of pediatric medulloblastoma have directed current and future research. This review highlights new developments in understanding the four molecular subtypes’ pathophysiology, epigenetics, and therapeutic targeting. In addition, we provide a focused discussion of recent developments in imaging, and in the surgery, chemotherapy, and radiotherapy of pediatric medulloblastoma. The article includes a brief explanation of healthcare costs associated with medulloblastoma treatment. Full article

(This article belongs to the Special Issue Childhood Brain Cancer Treatment)

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16 pages, 1452 KiB

Open AccessReview

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma

by Davis P. Argersinger, Sarah R. Rivas, Ashish H. Shah, Sadhana Jackson and John D. Heiss

Cancers 2021, 13(21), 5280; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215280 - 21 Oct 2021

Cited by 27 | Viewed by 8577

Abstract

H3K27M-mutant diffuse midline gliomas (DMGs) are rare childhood central nervous system tumors that carry a dismal prognosis. Thus, innovative treatment approaches are greatly needed to improve clinical outcomes for these patients. Here, we discuss current trends in research of H3K27M-mutant diffuse midline glioma. [...] Read more.

H3K27M-mutant diffuse midline gliomas (DMGs) are rare childhood central nervous system tumors that carry a dismal prognosis. Thus, innovative treatment approaches are greatly needed to improve clinical outcomes for these patients. Here, we discuss current trends in research of H3K27M-mutant diffuse midline glioma. This review highlights new developments of molecular pathophysiology for these tumors, as they relate to epigenetics and therapeutic targeting. We focus our discussion on combinatorial therapies addressing the inherent complexity of treating H3K27M-mutant diffuse midline gliomas and incorporating recent advances in immunotherapy, molecular biology, genetics, radiation, and stereotaxic surgical diagnostics. Full article

(This article belongs to the Special Issue Childhood Brain Cancer Treatment)

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