The Ras Tracker

For more than 20 years, Sharon Campbell, PhD, has been studying Ras, a protein implicated in 30 percent of all cancers. Now she’s on the hunt for alternative ways to shut the protein down.

The Ras Tracker click to enlarge Sharon Campbell, MD/Photo by Max Englund

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“Do you want to study molecules or do you want to help people?” This was the question Sharon Campbell’s grandfather, Morris Schwartz, MD, asked her when she told him she wanted to become a scientist. It was a loaded question, a last ditch effort to convince his granddaughter to take over his medical practice in upstate New York.

“He was a really respected, old-fashioned kind of general practitioner, the kind of doctor who would visit patients at their homes and accept eggs as payment,” says Campbell, a professor of biochemistry and biophysics in the UNC School of Medicine. “He was just an amazing guy. He wanted one of us to take care of the people he’d taken care of for so many years.”

But every single grandkid chose a different path. Campbell’s led her to UNC where she has become an internationally recognized expert on Ras, a protein that plays a major role in many cancers but has eluded researchers as a viable target for therapies.

Now, Campbell, a member of the Lineberger Comprehensive Cancer Center, is part of a National Cancer Institute initiative to stop Ras by alternative methods. For this and her years of research leading to a better understanding of the Ras and Rho families of proteins, she earned the 2014 Battle Distinguished Cancer Research Award, which recognizes exceptional cancer research at the UNC School of Medicine and comes with a $25,000 prize.

We sat down with Dr. Campbell to discuss her research and the NCI initiative dedicated to finding better ways to attack Ras, with the hope of helping millions of people who need better cancer therapies.

What drove you to pursue science as a career and graduate degrees from Yale?

Although my grandfather really wanted me to become a physician, a part of me was a little rebellious. I wanted to find my own way and not be told what to do. So I took standard courses at Rutgers University, a little bit of everything.  I really liked science. I became a physical chemistry major, conducted research as an undergrad, and really enjoyed it. I had a great, very supportive mentor named Barbara Zilinskas [PhD]. Having undergraduate research experience and a mentor like that was huge; it made me interested in pursuing graduate school.

I interviewed at several places and opted for Yale, which had one of best chemistry departments in the United States. It was in graduate school when I started working on protein that I still work on today – Ras.

Frank McCormick, who now heads the National Cancer Institute initiative on Ras, gave a talk at Yale about how they didn’t know the structure of the protein at that point, but they knew it was a prevalent oncogene that drives human cancer.

I became very excited about this, so I wrote an NIH postdoctoral proposal to study Ras by using [nuclear magnetic resonance] NMR spectroscopy, which can determine the structures of molecules in solution rather than in a crystalline state. This is important because in solution NMR can capture how molecules move. And with Ras, the critical regions of the protein move quite a bit.

I got funded, which was a little easier back then. These days it’s unusual for a grad student to write a proposal based on a concept with no data and get funded, and then join a lab as a postdoc.

As a postdoc at Brandeis University, I wound up publishing early results using NMR spectroscopy to study the Ras protein. Again, I had a great postdoc advisor, Alfred Redfield [PhD] who thought that if your ideas were your own then you should be the sole author even though he provided support for the lab. He insisted. So I wound up being the sole author on that paper.

5q-chem-bio-physThat must have garnered a lot of attention. Is that how you wound up at DuPont? What did you accomplish there?

Yes. I was a postdoc for only a year when I got a job at DuPont. It was a very interesting opportunity because the position was with DuPont’s central research and development division. There were about 100 scientists funded to work on things that weren’t tied to the company’s interests. It was like a mini think tank.

They were looking for someone to set up an NMR facility there and Ras was trendy. We developed novel techniques to be able to solve the structure of the protein. At the time, it was one of the largest proteins solved, and doing this was important because seeing how all the atoms of a molecule are coordinated to drive its cellular function, can help scientists think about how to devise therapies that might target the molecule.

One of the advantages of NMR is that we can see how different parts of a molecule move in relation to each other. This is key for Ras. And this movement is a big theme right now – how the dynamics of a protein are important for the protein’s function and how these dynamics can be used to facilitate drug discovery efforts.

I was at DuPont for three years. We worked in multidisciplinary teams of chemists, physicists, and biologists – all people with different outlooks. We all came to the table because we knew that complex problems sometimes require complex solutions.  I really liked this. I knew I would always want to be part of a multidisciplinary team. I didn’t want to work in a vacuum.

After three years, DuPont created a joint venture with Merck. Scientists in our group were told they had to work on problems tied to the company’s directives. At first, I thought that was fine. I worked on HIV proteases and other systems. But I really wanted to work on Ras. It was a system that I was inspired to work on from the start.

Also, many other people who prospered there went on to start their own companies or took academic appointments. We had a core group of great people and slowly they were leaving. The environment was changing.

As this was happening, I met Channing Der [UNC Kenan Distinguished Professor of pharmacology] at a conference. He said I should apply to UNC. I applied here and a few other places. But I really liked UNC most because I felt it was a highly collaborative environment. And I didn’t want to just do physics without the biology. I knew some of the people here and I knew they were very good, internationally recognized experts. So I joined UNC in 1994.

5q-proteinMuch of your focus remains on the Ras family of proteins. What is their role in cancer and what has your research shown?

There is a superfamily of over 150 proteins called the Ras superfamily. Ras, itself, was the founding member of this family. Within that superfamily, there are subclasses. And there’s a Ras subclass. And within that, there are three Ras isoforms: KRas, NRas, and HRas. KRas is particularly prevalent as a mutated protein in human cancers. When it gets mutated, the protein is chronically activated. It’s turned on and can’t get turned off.

These Ras proteins are critical signal-transducing proteins. That means they’re molecular switches. When turned on, they drive multiple cellular pathways that regulate cellular growth. Deregulated cellular growth is a hallmark of cancers.

But over the past 20 years, efforts to target Ras and create therapies for cancer patients haven’t been very productive. Ras doesn’t have a druggable surface.  Moreover, Ras binds its cofactor GTP with high affinity, so, unlike kinases, competitive nucleotide inhibitors will not work.

But now the National Cancer Institute has mounted a sizable effort to target Ras in novel ways. We think there are a lot of different ways to do this. For instance, if you can’t target the protein itself, then maybe we can target the kinases that are activated downstream of Ras and contribute to cancer growth or metastasis.

In my lab at UNC, we found different ways to modulate Ras function. That is, the protein gets modified after it’s been produced in a cell, and these modifications are key to driving tumor development. So if we can prevent the modifications from taking place, then this could be an alternative way to target Ras. And these modifications would include enzymes, which are easier to target than Ras. So, in essence, instead of targeting Ras, we’d target the events that promote Ras-mediated tumorigenesis.

5q-webEarlier this year your lab and collaborators found that two proteins – vinculin and actin – work together to promote cell movement. How do they do this and what does this mean in terms of understanding cancer metastasis?

Cells contain a matrix that gives rise to its shape and drives differentiation and movement. A key and abundant component of this matrix is actin.  F-actin is a polymer – [a chain of several actin units] – and it’s very dynamic. It makes these very long polymers and then crosslinks other actin polymers. And this creates a matrix that causes cells to adhere to a substrate. When actin undergoes directional polymerization and depolymerization, it causes cells to move.

Vinculin, another abundant protein, binds directly to actin. When vinculin binds, it helps actin network and adhere. If you lose vinculin function, cells don’t adhere as well and they move much quicker. That’s the hallmark of a tumor suppressor protein. So vinculin has been dubbed as such.

We generated a new model for how vinculin and actin interact and published it this year in the journal Structure.  However, as both vinculin and actin have many binding partners, it was unclear how important this particular interaction was. Based on our structural model, we were able to disrupt the actin-vinculin interface with a single mutation. We worked with Clare Waterman’s group at NIH to show [in the Journal of Cell Biology], that if we disrupt the ability of vinculin to directly associate with actin in cells, the cells move really quickly, similar to knocking down of vinculin itself. These observations indicate that the ability of vinculin to directly engage actin is key for driving cell motility.

This is important because a lot of cancers are treatable but much less so once they metastasize.

Both Ras and vinculin contribute to deregulated cell growth, movement, formation, and structure.

5q-asking-purpleHow do you think Ras research will move forward in the coming years?

One thing that’s important is the new NCI effort targeting Ras. The NCI is trying to get the NIH, industry scientists, and academic scientists all working together and communicating better. There are a lot of companies working on Ras but we don’t know what they’ve done because a lot of their studies haven’t been published.

This initiative is a way to say, Ras is one of the most critical proteins in human cancers; we need to put a huge effort into this to hopefully find an anti-cancer agent that down regulates Ras in cancer. But for that to happen we need to open communication channels so scientists will talk more. This started last August. NCI set up resources and a new website to increase communication. They’re sending cell lines to scientists, conducting screenings, etc. I’m on the NIH Ras working group, which met for the first time last year.

I think this is exciting because the more we communicate, the more we’ll understand the complexities associated with Ras signaling. Turns out there are so many Ras pathways; the more we know about them, the more opportunities will arise to create potential therapies.

Ras is considered the molecule of the year right now; lot of attention is being devoted to it, which is exciting. There were four meetings this year dedicated to Ras. I organized one of them. So, I’m cautiously optimistic that if we put a lot of expertise and minds together, then something is going to come out of this. 

By studying novel ways that Ras ‘molecules’ cause cancer, we hope to identify new anti-cancer therapies and help people. While my path has diverged from the one my grandfather would have chosen for me, I think he would approve, as we share a common goal.

Read more about Dr. Campbell’s work on her webpage.

Read more about the Battle Award announcement.

Media contact: Mark Derewicz, UNC School of Medicine, mark.derewicz@unchealth.unc.edu, 919-923-0959.

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