Valproic acid helpful for GBM, but not for lower grades?
Valproic acid, compared to other antiepileptic drugs, is associated with improved overall and progression-free survival in glioblastoma but worse outcome in grade II/III gliomas treated with temozolomide
Please keep in mind this was a retrospective study (and therefore not definitive), but it does suggest VPA might not be the best choice for lower grade glioma therapeutic drug cocktails.
This one perplexes me a bit. The IDH1 mutation is a common difference between glio and lower grades, so I often consider that when outcomes are different between the two. The IDH1 mutation often leads to hypermethylation, and, if I recall my discussion with my NO correctly, the HDAC inhibition from VPA is a theoretically good way to try to reduce that hypermethylation.
In the paper, I see in Table 1 that out of 20 lower grade IDH1 mutated patients, only 4 were taking VPA. In fact, even in GBM patients, 7 out of the 8 IDH1 mutated patients were not taking VPA.
That makes me feel a bit better about Bernie taking VPA with an IDH1 mutated GBM.
Unfortunately only 57% of the no valproic acid group and 35% of the valproic acid group were tested for IDH1 status. So the true rate of IDH1 muatations in both of these groups might be very different from the 31.4% and 25% shown in Table 1.
Nevertheless, the shorter median survival in the valproic acid group could very well simply be an artifact of there being a larger percentage of patients with IDH1 mutation in the no valproic acid group, giving that group an inherent survival advantage regardless of valproic acid use.
I'm not so sure that valproic acid would necessarily reduce overall methylation levels. Its effect on DNA methylation may be complicated, as suggested by this study.
"Our studies showed that inhibition of HDAC blocked cell proliferation and cell cycle progression in relation to alteration in cancer-related genes, increased overall DNA methylation, and decreased methylation of tumor suppressor genes.
Expression patterns of cancer-related genes were modulated by VPA. The expression of THBS1, CASP8, SPARC, CDKN1A, HIC1, CDKN1B, and HIN1 was upregulated, and that of MYCN and TIG1 was downregulated."
Stephen,
ReplyDeleteThis one perplexes me a bit. The IDH1 mutation is a common difference between glio and lower grades, so I often consider that when outcomes are different between the two. The IDH1 mutation often leads to hypermethylation, and, if I recall my discussion with my NO correctly, the HDAC inhibition from VPA is a theoretically good way to try to reduce that hypermethylation.
In the paper, I see in Table 1 that out of 20 lower grade IDH1 mutated patients, only 4 were taking VPA. In fact, even in GBM patients, 7 out of the 8 IDH1 mutated patients were not taking VPA.
That makes me feel a bit better about Bernie taking VPA with an IDH1 mutated GBM.
Best,
Kendall
Unfortunately only 57% of the no valproic acid group and 35% of the valproic acid group were tested for IDH1 status. So the true rate of IDH1 muatations in both of these groups might be very different from the 31.4% and 25% shown in Table 1.
ReplyDeleteNevertheless, the shorter median survival in the valproic acid group could very well simply be an artifact of there being a larger percentage of patients with IDH1 mutation in the no valproic acid group, giving that group an inherent survival advantage regardless of valproic acid use.
I'm not so sure that valproic acid would necessarily reduce overall methylation levels. Its effect on DNA methylation may be complicated, as suggested by this study.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710400/
"Our studies showed that inhibition of HDAC blocked cell proliferation and cell cycle progression in relation to alteration in cancer-related genes, increased overall DNA methylation, and decreased methylation of tumor suppressor genes.
Expression patterns of cancer-related genes were modulated by VPA. The expression of THBS1, CASP8, SPARC, CDKN1A, HIC1, CDKN1B, and HIN1 was upregulated, and that of MYCN and TIG1 was downregulated."