SGK1 enzyme, asthma and cancer therapies: an interview with Dr. Jonathan D. Powell, Johns Hopkins Kimmel Cancer Center

Published on May 13, 2014 at 9:33 AM · No Comments

Interview conducted by , BA Hons (Cantab)


Dr. Jonathan D. Powell
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What is the SGK1 enzyme and what pathways is it involved in?

SGK1 stands for serum/glucocorticoid-regulated kinase 1. SGK1 is a member of the AGC kinase family, which is a huge family of kinases.

We really only know a lot about the major members of this family such as Akt and S6K1 and it is interesting to think that we are only at the tip of the iceberg in terms of defining the function of all the individual members.

What sparked your interest in SGK1?

It was a very logical step for our lab, which had previously shown that mTOR signaling played a very important role in T cell differentiation.

In particular, TOR complex 1 and TOR complex 2 had differential effects on T cell activation and differentiation.

The reason we became interested in SGK1 is because it had previously been shown that SGK1 is activated by mTOR complex 2.

Could you please outline your recent research that looked at mice missing the enzyme SGK1?

As mentioned, the lab had previously shown that mTOR2 was involved in the regulation of T helper cells, in particular the Th2 cells that produce IL-4, IL-5, IL-13. These interleukins are not only involved in defending against parasites, for example, but also play a role in allergic diseases such as asthma.

We therefore hypothesized that because SGK-1 is activated by TOR2, it may be the downstream mediator involved in regulating the T cell response.

We therefore studied a knockout SGK-1 model (where everything was intact except for SGK-1) and we found that the cells no longer readily became Th2 cells, but had properties of the Th1 cell instead.

What were the main findings of this study?

The main finding is that SGK1 is a critical regulator downstream of mTOR that regulates T helper cell differentiation.

How do you think these results can be explained?

The mechanics of this are very interesting because as well as SGK1 promoting the established signaling for Th2 cells, it also simultaneously suppresses the signaling for Th1 cells. SGK1 therefore performs two functions that together have the net desired effect of making a Th2 cell.

Do you think it will be possible to develop a drug that blocks the SGK1 enzyme? Is this likely to have the same effects as missing the enzyme altogether?

Actually, a drug does already exist as a result of previous studies into SGK1. These initial studies into SGK1 focused on its role in regulating sodium excretion in the kidney.

Drug companies in particular, were excited by the prospect that through regulation of SGK1, blood pressure could potentially be regulated.

As far as I know, that didn't turn out to be particularly effective, but we're now very excited about investigating the effects of these inhibitors on immune function.

What would be the main hurdles in adjusting the current drug to make it applicable for this target?

I don't know that there are any hurdles, but, as I mentioned before, in our studies, we selectively inhibited SGK1 only in the T cells. Therefore, a big question is whether the drug would be as effective when it also involves other cells in the body. Having said that, the good news is that the drug has been tested in animals and nothing bad has happened.

Is blocking the SGK1 enzyme likely to have any significant negative effects?

As far as we can tell, the answer is no, which is kind of exciting. We have a basic scientific finding that really lends itself to a drug, but that's the next step.

What are your further research plans with regards to SGK1?

For me, one of the really exciting aspects of this research is the idea that you can selectively regulate the immune system.

For problems like asthma and other autoimmune diseases, what we usually do is just suppress the immune system completely. Of course, that leaves a person very susceptible to infections and other problems. Therefore, what's really exciting is the idea that by targeting this specific enzyme, we may be able to regulate the immune system to not do one thing and block something like asthma, for example, while at the same time leaving the rest of the immune system intact. This is one of the areas that we're actively pursuing.

Another really interesting aspect of this research is the idea that SGK1 inhibition could enhance theTh1 immune response. We're very excited by the possibility of using an inhibitor of SGK1 to enhance cancer immunotherapy, or even just vaccines in general.

On the one hand you could use the drug to inhibit asthma in a patient and on the other, you could give that same drug to someone who's receiving immunotherapy for cancer and it could actually enhance their immune response against the cancer. For me, that absolutely reflects what we want to do in terms of immunology, which is to selectively regulate the immune response.

How was your research funded?

We were funded by the American Asthma Foundation. Their modus operandi is to fund projects of people who have no experience in asthma. The idea is that, if they fund something that's important and interesting, ultimately, in the end, it will be useful.

I think our work is really the poster child of that concept as we approached this from the point of view of our own research and what we were interested in, and they saw the potential value in it and in the end, we may actually have revealed a new line of inquiry in terms of developing new drugs.

Where can readers find more information?

For more information on the American Asthma Foundation: http://www.americanasthmafoundation.org/

For more information on Johns Hopkins and our research: http://www.hopkinsmedicine.org/news/media/releases/enzyme_revealed_as_promising_target_to_treat_asthma_and_cancer

About Dr Jonathan D. Powell

Jonathan Powell received his AB from Dartmouth College and his M.D. Ph.D. from Emory University School of Medicine. His Post-graduate clinical training included the Osler Internal Medicine Residency Program at Johns Hopkins and Fellowship training in Hematology-Oncology at The Brigham and Women’s Hospital in Boston and NHLBI at the NIH.

Prior to joining the Faculty at Johns Hopkins Dr. Powell was a post-doctoral fellow in the Laboratory of Dr. Ronald Schwartz at the NIH. Dr. Powell’s lab is interested in studying the cellular, biochemical and molecular mechanisms surrounding T cell activation, differentiation and tolerance.

Specifically, the lab has generated a number of genetically altered mice to determine the role of the mTOR signaling pathway in directing effector and regulatory T cell differentiation.

In addition, the lab has used these mice to probe the role of mTOR in influencing T cell responses in vivo in viral, auto- and tumor immunity. These findings have been translated to developing tolerance inducing protocols in the setting of bone marrow transplantation.

Further, based on the biochemical insight gained from dissecting mTOR signaling in lymphocytes, the lab has been targeting metabolic pathways as a means to inhibit mTOR signaling in order to treat cancer and has revealed novel pathways regulating glucose metabolism and the generation of brown fat.

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