SHH medulloblastoma treatment [Neurosurgery Wiki]

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====== SHH medulloblastoma treatment ======

For patients whose tumors are driven by mutations in the [[sonic hedgehog]] (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated [[medulloblastoma]]s do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated medulloblastoma
((Kieran MW. Targeted treatment for sonic hedgehog-dependent medulloblastoma.
Neuro Oncol. 2014 Aug;16(8):1037-47. doi: 10.1093/neuonc/nou109. Review. PubMed
PMID: 24951114; PubMed Central PMCID: PMC4096181.
)). 

One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPC). 
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Data provide strong evidence that [[Quisinostat]] or other class I HDAC inhibitors might be therapeutically useful for patients with SHH MB including those resistant to SMO inhibition
((Pak E, MacKenzie EL, Zhao X, Pazyra-Murphy MF, Park PMC, Wu L, Shaw DL,
Addleson EC, Cayer SS, Lopez BG, Agar NYR, Rubin LL, Qi J, Merk DJ, Segal RA. A
large-scale drug screen identifies selective inhibitors of class I HDACs as a
potential therapeutic option for SHH medulloblastoma. Neuro Oncol. 2019 May 16.
pii: noz089. doi: 10.1093/neuonc/noz089. [Epub ahead of print] PubMed PMID:
31111916.
)).
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Markant et al., previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent medulloblastoma. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2-M phases of the cell cycle. They show that CD15(+) cells progress more rapidly through the cell cycle than CD15(-) cells and contain an increased proportion of cells in G2-M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora kinase (Aurk) and Polo-like kinases (Plk), key regulators of G2-M, induces cell-cycle arrest, apoptosis, and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived medulloblastoma xenografts are also sensitive to Aurk and Plk inhibitors. The findings suggest that targeting G2-M regulators may represent a novel approach for treatment of human medulloblastoma
((Markant SL, Esparza LA, Sun J, Barton KL, McCoig LM, Grant GA, Crawford JR,
Levy ML, Northcott PA, Shih D, Remke M, Taylor MD, Wechsler-Reya RJ. Targeting
sonic hedgehog-associated medulloblastoma through inhibition of Aurora and
Polo-like kinases. Cancer Res. 2013 Oct 15;73(20):6310-22. doi:
10.1158/0008-5472.CAN-12-4258. PubMed PMID: 24067506; PubMed Central PMCID:
PMC3800039.
)).