Silmitasertib
The US Food and Drug Administration (FDA) has granted rare paediatric disease designation and fast track designation for silmitasertib in the treatment of recurrent sonic hedgehog (SHH) medulloblastoma. Silmitasertib is a protein kinase inhibitor of casein kinase 2.[63]Marschke RF, Borad MJ, McFarland RW, et al. Findings from the phase I clinical trials of CX-4945, an orally available inhibitor of CK2. J Clin Oncol. 2011 May 20;29(15):3087. One US clinical trial to assess the safety and tolerability of this drug in patients with refractory medulloblastoma is ongoing.
Personalised treatment
Studies are beginning to utilise tumour biological profile to stratify patients according to risk criteria.[64]Juraschka K, Taylor MD. Medulloblastoma in the age of molecular subgroups: a review. J Neurosurg Pediatr. 2019 Oct 1;24(4):353-63.
https://thejns.org/pediatrics/view/journals/j-neurosurg-pediatr/24/4/article-p353.xml?tab_body=fulltext
http://www.ncbi.nlm.nih.gov/pubmed/31574483?tool=bestpractice.com
[65]Menyhárt O, Giangaspero F, Győrffy B. Molecular markers and potential therapeutic targets in non-WNT/non-SHH (group 3 and group 4) medulloblastomas. J Hematol Oncol. 2019 Mar 15;12(1):29.
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-019-0712-y
http://www.ncbi.nlm.nih.gov/pubmed/30876441?tool=bestpractice.com
[66]El Doussouki M, Gajjar A, Chamdine O. Molecular genetics of medulloblastoma in children: diagnostic, therapeutic and prognostic implications. 25 Jan 2019 [internet publication].
https://www.futuremedicine.com/doi/full/10.2217/fnl-2018-0030
[67]Iv M, Zhou M, Shpanskaya K, et al. MR imaging-based radiomic signatures of distinct molecular subgroups of medulloblastoma. AJNR Am J Neuroradiol. 2019 Jan;40(1):154-61.
http://www.ajnr.org/content/40/1/154.long
http://www.ncbi.nlm.nih.gov/pubmed/30523141?tool=bestpractice.com
Novel targeted therapies to personalise treatment and reduce toxicity have been of great interest since the four major molecular subgroups of medulloblastoma were identified, one of which is characterised by activation of the SHH pathway. Pre-clinical data suggest that inhibitors of the SHH pathway could become valuable treatment options for patients with this subgroup of medulloblastoma.[68]Lee MJ, Hatton BA, Villavicencio EH, et al. Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model. Proc Natl Acad Sci USA. 2012 May 15;109(20):7859-64.
https://www.pnas.org/content/109/20/7859.long
http://www.ncbi.nlm.nih.gov/pubmed/22550175?tool=bestpractice.com
Much more work is required before broad-based clinical applications can be made toward the treatment of medulloblastomas.[69]Gerber NU, Mynarek M, von Hoff K, et al. Recent developments and current concepts in medulloblastoma. Cancer Treat Rev. 2014 Apr;40(3):356-65.
http://www.ncbi.nlm.nih.gov/pubmed/24389035?tool=bestpractice.com
[70]Samkari A, White JC, Packer RJ. Medulloblastoma: toward biologically based management. Semin Pediatr Neurol. 2015 Mar;22(1):6-13.
http://www.ncbi.nlm.nih.gov/pubmed/25976255?tool=bestpractice.com
Pencil beam scanning proton therapy
Pencil beam scanning proton therapy, a more advanced type of proton therapy, has demonstrated good tumour control and low toxicity rates among children/adolescents with brain tumours.[71]Vázquez M, Bachmann N, Pica A, et al. Early outcome after craniospinal irradiation with pencil beam scanning proton therapy for children, adolescents and young adults with brain tumors. Pediatr Blood Cancer. 2023 Feb;70(2):e30087.
http://www.ncbi.nlm.nih.gov/pubmed/36377685?tool=bestpractice.com
[72]Tran S, Lim PS, Bojaxhiu B, et al. Clinical outcomes and quality of life in children and adolescents with primary brain tumors treated with pencil beam scanning proton therapy. Pediatr Blood Cancer. 2020 Dec;67(12):e28465.
http://www.ncbi.nlm.nih.gov/pubmed/32902137?tool=bestpractice.com
Chemotherapy intensification and/or radiation enhancers
Trials for high-risk patients include dose intensification of chemotherapy and/or the use of radiation enhancers in an attempt to improve survival. As of yet, only concurrent carboplatin with craniospinal irradiation (CSI) for high-risk group 3 medulloblastoma has shown to be of significant clinical benefit.[60]Leary SES, Packer RJ, Li Y, et al. Efficacy of carboplatin and isotretinoin in children with high-risk medulloblastoma: a randomized clinical trial from the children's oncology group. JAMA Oncol. 2021 Sep 1;7(9):1313-21.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8299367
http://www.ncbi.nlm.nih.gov/pubmed/34292305?tool=bestpractice.com
Immunotherapy
A number of clinical trials investigating the safety and efficacy of immunotherapy for recurrent medulloblastoma are ongoing, including oncolytic virus immunotherapy, immune checkpoint inhibitor and other immunomodulatory therapies, vaccine or RNA therapy, and chimeric antigen reception (CAR) T-cell and other cellular therapies.