Transition to exhaustion: clues for cancer immunotherapy

Research on immune cells “exhausted” by chronic viral infection provides clues on how to refine cancer immunotherapy. The results were published Tuesday, Dec. 3 in Immunity. Scientists at Emory Vaccine Center, led by Rafi Ahmed, PhD, have learned about exhausted CD8 T cells, based on studying mice with chronic viral infections. In the presence of persistent virus or cancer, CD8 T cells lose much of their ability to fight disease, and display inhibitory checkpoint proteins Read more

Radiologists wrestle with robots - ethically

Emory bioethicist John Banja says: don’t believe the hype about AI replacing Read more

Opioids: crunching the Tweets

The aim is to be able to spot patterns of overdoses faster than prescription drug monitoring Read more

valproate

Valproate: epigenetic solvent

Oncologist Johann Brandes and colleagues from Winship Cancer Institute have a recent study on the preventive effects of valproate, now prescribed for epilepsy and bipolar disorder, against head and neck cancer.

Published in Cancer, it was a clever example of number crunching, using data from the Veterans’ Administration. If you want to know about the anticancer effects of a widely used drug, check who’s already taking it for another reason (25,000 veterans were taking it). The results suggest that valproate – OR a drug that works with a similar mechanism – might be used to prevent head and neck cancer in patients who are at high risk. Also see this related paper from Brandes and colleagues on chemoprevention in lung cancer.

However, any examination of valproate should take into account neurologist Kim Meador’s work on antiepileptic drugs taken by pregnant women — he was at Emory for several years but recently moved to Stanford. His work with the NEAD study definitively showed that valproate, taken during pregnancy, increases the risk of birth defects and intellectual disability in children.

There’s even more about valproate: it might help tone-deaf adults learn to differentiate musical tones, according to one study. It has been used to enhance the reprogramming of somatic cells into induced pluripotent stem cells. It seems that valproate just shakes things up, turning on genes that have been off, erasing decisions that cells have already made.

Valproate is a tricky drug, with several modes of action: it blocks sodium channels, enhances the effects of the inhibitory neurotransmitter GABA, and inhibits histone deacetylases. Although the first two may be contributing to the antiepileptic effects, the last one may be contributing to longer-lasting changes. Histone deacetylases are a way a cell keeps genes turned off; inhibit them and you loosen things up, allowing the remodeling of chromatin and unearthing genes that were silenced.

In tumors, genes that prevent runaway growth are silenced. It may be that valproate is loosening chromatin enough to allow the growth control machinery to reemerge, although the effects observed in the Brandes paper are specific for head and neck cancer, and not other forms of cancer. The data suggest that valproate has a preventive effect with respect to smoking-related cancers and not viral-related cancers.

With adults at high risk of cancer recurrence, side effects from valproate may be more acceptable than in other situations. Even so, with follow-up research, it may be possible to isolate where the anticancer effects of valproate come from – that is, which histone deacetylase in particular is responsible – find a more specific drug, and avoid potential broad side effects.

Posted on by Quinn Eastman in Cancer, Neuro Leave a comment