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Friday, February 10, 2017

3 Questions… A Better Way to Target RAS

With John P. O'Bryan, PhD, of University of Illinois College of Medicine

By Sarah DiGiulio

The RAS family of proteins is an attractive one—as far as cancer biologists are concerned. Mutations for genes in the RAS family are found in nearly 30 percent of all cancers. And they're highly prevalent in some of the most common cancers including colon, lung, and pancreatic cancer, as well as melanoma. Discovering or creating a drug to target RAS would be a big deal.

Now a group of researchers at the University of Illinois at Chicago say a new synthetic binding protein they created in the lab may put them one step toward that goal.

"Developing a RAS inhibitor has been the holy grail of cancer biology," noted John P. O'Bryan, PhD, Associate Professor of Pharmacology in the University of Illinois College of Medicine. "We did not look for a drug or specifically for an inhibitor," O'Bryan said about the new study from he and his colleagues.

"We used monobody technology, a type of protein-engineering technology, to identify regions of RAS that are critical for its function."

In an interview with Oncology Times, O'Bryan further explained why his group decided to investigate monobodies and how they interact with RAS—and why these new findings put translational oncology one step closer to an effective RAS inhibitor.

1. What is new about the findings from this study?

"Our work revealed for the first time the importance of the α4-β6-α5 region of RAS for [RAS] function. Our studies found that an engineered protein called NS1 monobody binds that α4-β6-α5 interface on RAS and actually blocks RAS's oncogenic and signaling ability—which is quite surprising since it didn't seem to interfere with the ability of RAS to interact with its downstream targets. This new area potentially could be used as a way to therapeutically inhibit RAS in the future.

"Also, this work demonstrated for the first time that RAS actually interacts with itself to activate its downstream targets. And that's been a question in the literature for quite a few years now—how RAS activates its downstream targets. This research provides some of the first strong evidence that there is indeed RAS-RAS interaction that is important for activation of downstream effectors."​

2. What is the NS1 monobody and why did you decide to try using it to interfere with RAS instead of looking at another way of interfering with RAS?

"NS1 is a new [monobody]. Monobody techonology was actually developed by our collaborator Dr. Shohei Koide (who was previously at the university and a coauthor on this paper).

"So, monobodies are engineered proteins. They're much smaller than antibodies, which are very difficult to use within cells because of the reducing potential inside a cell. Monobodies in contrast lack disulfide bonds and are, therefore, resistant to the reducing environment of the cell. They're much easier to work with in terms of expressing them in cells and targeting them to your protein of interest. So they're much easier to genetically encode— to use as a way of targeting the pathway of interest, in this case RAS.

"We isolated a monobody that could specifically recognize RAS and it turned out that it actually inhibits RAS signaling and oncogenic activity. Monobodies have been around for a while, but this monobody to RAS is quite new and quite specific—and turned out to be very interesting in its ability to block RAS function."

3. What's the next step—how do you use this research to develop a drug that targets all these cancers with mutated RAS proteins?

"That's the million-dollar question. RAS is mutated in roughly 30 percent of human tumors. So we think it's a very important target for developing drugs that will block its function. RAS has not been a very good target for inhibiting because it's more like a little ball without very deep pockets that inhibitors typically like to sit in. So it's been very challenging to inhibit the protein with small molecules.

"There are RAS inhibitors that have been developed: small molecule inhibitors. But those have not proven very effective clinically. There are others that are being developed that target other areas of the protein. But no one has really targeted an interface at this point. So it raises the question of whether we can actually design novel inhibitors to this region that will block RAS function.

"The strategy that we're taking is to try to use the information that we know from how NS1 binds to RAS to see if we can exploit that for developing small molecules that bind in that same region and may then act as inhibitors to the protein. Such inhibitors would actually be more appealing than NS1 itself because—although [NS1] is small—in terms of a drug it's actually quite large. So it's difficult to deliver sufficient quantities into cells of a patient to inhibit RAS. Whereas if we can develop a small molecule that can more easily penetrate cells of tumors—that would be more likely to work as a therapy.

"In terms of time frame for that, with a little bit of luck, hopefully we'll have some in a few years. But that remains to be seen."