AACR 2016

p62: Metabolism and the tumour microenvironment

Prof Jorge Moscat - Sanford Burnahm Prebys Medical Discovery Institute, La Jolla, USA

p62 was cloned in my laboratory many years ago and was later found to be a substrate of autophagy but it’s much more than that, it’s actually a detoxifying molecule. When autophagy is functional, p62 brings [?? 0:21], these folded proteins to damage organelles so they’re out of the autophagosome for degradation and therefore should detoxify cells from reactive oxygen species. But during that process the creation of nutrients serves for p62 to also sense the nutrient state of the cell and activate mTOR and proliferation. So most cancer cells, particularly hepatocytes in the liver, they have up-regulated p62 as a consequence of liver damage, autophagy inhibition, oncogenic stimuli and therefore p62 plays a role in activating mTOR proliferation and at the same time it detoxifies cells from reactive oxygen species. So it’s a combination of two things – reduction in cell death and promoting survival through Nrf2 autophagy and the activation of the mTOR pathway promotes the whole proliferation that accounts for, for example, hepatocellular carcinoma initiation and progression.

How can one approach this in a clinical setting?

There are many ways you can do that; p62 is a scaffold protein and obviously it’s not druggable. However, p62 binds to a number of kinases and transcription factor activators that can be targeted. For example, p62 binds a kinase called MEK kinase 3 that my laboratory showed is critical for the activation of mTOR. There is an active programme in my institute aimed at blocking the MEK kinase 3 activity as part of the p62 mechanistic complex in order to prevent mTOR activation. So the idea is that if you block mTOR then you will block the capacity of these cells to grow. On the other hand, you can also block the ability of p62 to bind with the autophagosome or the ability of p62 to bind other adaptors like this protein called Keap1 that regulates Nrf2 that is a RAW [?] scavenger. So we have a programme in the institute aimed at identifying molecules that will target p62 at different mechanisms and we expect that those in vivo will produce a reduction in tumorigenesis. We know that happens in vitro, in cell cultures, and we know that in genetically modified mouse models the loss of p62 prevents hepatocellular carcinoma.

Working around it?

Exactly, so the idea is to have a different hit that p62 is controlling, we want to really block each of them differently based on or instructed by the data we have in the knock-out mice.

Have any adverse effects been reported?

Actually you don’t know until you run a phase I clinical trial but the interesting thing is that in knock-out mice they don’t have a toxic phenotype, they are perfectly normal. The idea is that the only thing they have is that they develop [?? 3:21] over time. But the idea is that p62 under normal conditions can be made redundant by other autophagy adaptors like NBR1 and then the function of p62 is not so essential. However, in cancer p62 is dramatically upregulated whereas the other autophagy adaptors have not, then in cancer it becomes absolutely essentially. So cells become addicted to p62 whereas normal cells don’t care because they have other adaptors.

Are you close to beginning some clinical trials?

No, we are still far away from that and we have hits, we have [?? 4:01] compounds. But the aspiration is to really go to the clinic in the future. Right now we have a lot of preclinical data, very solid mouse models of different cancers. Right now we are much more interested in the progression from NAFLD, non-alcoholic fatty liver disease, to non-alcoholic steatohepatitis and hepatocellular carcinoma because in our country, as you know, obesity is epidemic and one of the consequences of obesity is the development of a fatty liver and a fatty liver is the first stage towards hepatocellular carcinoma as a risk factor. So we are trying to use p62, or better to block p62, to try to prevent the transition from NAFLD or steatosis to hepatitis and from hepatitis to hepatocellular carcinoma. Once the hepatocellular carcinoma is established blocking p62, we have shown, is sufficient to prevent progression of the tumour. So we’re addressing p62 in those three levels.