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Sunday, March 7, 2021

Academics & Research

Q&A: UH researcher wins American Cancer Society grant


frigo

Frigo got his doctorate in molecular and cellular biology from Tulane University in 2003. He is also a postdoctoral fellow at the Duke University Medical Center.  | File photo/ The Cougar

Assistant biology and biochemistry professor Daniel Frigo has been investigating prostate cancer research for the majority of his time at UH.  

Frigo recently received a $792,000 grant from the American Cancer Society to aid his research as it enters pre-clinical stages and shifts focus to the role of autophagy in prostate cancer.

The Cougar sat down with Frigo to discuss the grant and his research.

The Cougar: Where did you get the idea for this project?

Daniel Frigo: There has been some evidence that suggests that this particular process (autophagy) plays a role in other types of cancers, and now people have found that there’s drugs that can inhibit this process. They think of this process as a double-edged sword because early on it can function as a potential tumor suppressor, but later on it flips its role and drive cancer.

But the fact that it’s a druggable process means that there’s something you could do about it from a treatment perspective.  So an explanation as to how this process is occurring hasn’t really been examined in prostate cancer.

There have been people wanting to start clinical trials to block autophagy in late-stage prostate cancer, but the experiments done weren’t truly evaluating whether this was important in prostate cancer and, if so, at what stage and what is causing this process.

This concept of autophagy is used by a number of cells within the body, so there’s also this concern that if you broadly knock out or inhibit autophagy throughout the body there may be toxic side effects.

One of the things we thought we could do is use this preliminary data that suggests that there’s unique reasons this is being increased in the prostate, and so if we could hunt down some of these pathways then we may be able to block this process — but in a more selective manner and only in terms of the cancer and not broadly inhibiting autophagy throughout the body.

We thought there may be room for improvement.  Some of the initial results from clinical trials have come back in other cancers.

 

TC: What will this grant allow you to do with your research?

DF: It will help us validate whether autophagy plays a bona-fide role in this disease because it’s still uncertain whether it does, when it does and how it does. If it doesn’t play a role then hopefully we can eliminate any unnecessary pre-clinical trials.

If we discover that it does play a role, that lays the foundation for future studies where companies and medicinal chemists can figure out a way to target this and develop a drug that inhibits the process.  

After this core fundamental stage, the hope is that if we see positive or encouraging results, we transition into the translational phase. This stage prepares it to go into clinical trial.

TC: How long did it take to develop your research?

DF: This is something that probably started the first or second year that I came here in 2010 or 2011. Our first lab paper was over autophagy and prostate cancer. I would say this lab work first started it, we just had develop it further before we were able to “sell” our idea to the funding agencies.

TC: What role does autophagy play in cancer?

DF: Autophagy is kind of like this cellular recycling mechanism. People have suggested that this process is important in prostate cancer, but that had never truly been validated using genetic and molecular approaches.  

A lot of times people will do experiments that have only show that autophagy is somehow affecting cancer, but they haven’t been able to exactly pinpoint exactly what cause it has on cancer.  We wanted to knock down key components of this process in both preclinical cell models and also animals’ models.  

Essentially, we want to test the role, see if it’s potentially druggable and seeing if we can figure out at what stage, if it does play a role, it is important for and also figuring out how it regulated.

TC: Did your research begin with prostate cancer or the process of autophagy?

DF: We were working on prostate cancer first. Prostate cancer is an extremely prevalent cancer in men, and there’s a certain late stage in prostate cancer that is incurable. We really wanted to find out what was driving and advancing the late stages of this disease and why is it so hard to get rid of this cancer.  

Our proposal is that autophagy may be part of the answer in what is driving the more aggressive late stages of the disease. We came upon this after studying a particular signaling pathway that we knew was elevated in advanced cancer.  

One of the known processes of this signaling pathway was autophagy. It turns out that the regulation in prostate cancer is a bit more complex and that there isn’t just one signaling pathway and there’s actually three or four.  

TC: What role, if any, does autophagy play in other cancers?

DF: Its role has actually been tested better in a number of other types of cancer like pancreatic cancer, ovarian cancer, etc. Whether or not it plays a bona-fide role in every single one of these cancers is still up for debate.  

Some people think that because of its role as a recycling mechanism, the cells rely less on the outside environment because of its ability to degrade some of its own intracellular components and use that to produce both energy and building blocks. So, it becomes more resistant to the outside environment and because that it’ll be less responsive to things like chemotherapy and drugs.  

It’s an interesting hypothesis that if you can block that resistance mechanism then you can give an inhibitor of autophagy along with chemotherapy — then you can block the cancer cell’s escape mechanism.  

Because of this rationale, people became interested in testing this in late-stage cancer because there really aren’t that many other options. There’s actually this drug that’s been used for years in the treatment and prevention of malaria called chloroquine and it’s been shown that one of the side effects of this drug is that it can block autophagy.  

Since it’s been prominently used in the clinic, people have set up all these clinical trials to repurpose this drug for the treatment of prostate cancer. However, all of these results from this trials have come back and shown that you can’t really use this specific type of drug to effectively block autophagy in cancers without raising the level.

However, the level that they’re at now is causing toxicity; we will need to find out better ways to block autophagy if it is affecting it.

[email protected]


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