20.109(F11): Synthetic Lethality in Treating Medulloblastoma

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Synthetic Lethality in Treating Medulloblastoma

References

This review talks about the methods of inflicting HR deficient, cancerous cells with a synthetically lethal phenotype. When cells are unable to undergo HR, they rely on PARP-1 for DNA replication. If these deficient cells can be given a PARP-1 inhibitor, they will be unable to replicate DNA and undergo apoptosis.

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  • Daniel RA, Rozanska AL, Mulligan EA, Drew Y, Thomas HD, Castelbuono DJ, Hostomsky Z, Plummer ER, Tweddle DA, Boddy AV, Clifford SC, Curtin NJ. (2010). Central nervous system penetration and enhancement of temozolomide activity in childhood medulloblastoma models by poly(ADP-ribose) polymerase inhibitor AG-014699. British Journal of Cancer. 103(10), 1588-1596. http://www.nature.com/bjc/journal/v103/n10/full/6605946a.html.

Temozolomide is an alkylating agent that acts against medulloblastoma. PARP-1 has been shown to enhance this agent's activity. This paper assesses the effects of a specific PARP inhibitor on temozolomide-inhibited medulloblastoma.

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  • Tanori, M., Mancuso, M., Pasquali1, E., Leonardi, S., Rebessi, S., Majo, V.D., Guilly, M.N., Giangaspero, F., Covelli, V., Pazzaglia, S., Saran, A. (2008). PARP-1 cooperates with Ptc1 to suppress medulloblastoma and basal cell carcinoma. Carcinogenesis, 29(10), 1911–1919. http://carcin.oxfordjournals.org/content/29/10/1911.full.pdf.

This paper discusses PARP-1's effects on the "sonic hedgehog" development pathway. The patch protein (Ptc1) is a negative regulator for the development pathway and developmental defects occur when it is altered. To test for the interaction between PARP-1 and Ptc1, PARP-1 null mice were crossed with Ptc1 heterozygous ones. It was shown that PARP-1 inactivation makes brain cells more sensitive to radiation.

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Frappart et al discuss the role of BRCA2 in brain development. BRCA2 loss affects neural development, especially during embryonic and postnatal development. As such, BRCA2 can be considered a potent medulloblastoma inhibitor.

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This paper discusses a new Medulloblastoma model in which tumors arise in p53 and PARP deficient mice. Medulloblastoma is strongly inhibited by drugs blocking the hedgehog pathway. The paper also discusses some of the genetics behind the cancer.

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