Dr. Annette Khaled is the Head of the Division of Cancer Research in the Burnett School of Biomedical Sciences of the College of Medicine at University of Central Florida, Orlando, FL. Building on a strong foundation of research “firsts” beginning with her training at the National Cancer Institute, Dr. Khaled's lab recently discovered a novel peptide (CT20p) that causes cancer-specific cell death. BCRF recently spoke with Dr. Khaled about her research and her perspectives on the future of breast cancer.
Coming full circle and back to discovery research
I am an immunologist by training. My interest in breast cancer really grew from meeting our local donors, most of whom had some connection to breast cancer either as patients or as loved ones of patients. They really helped me to understand the patient perspective and the urgency breast cancer patients feel. I am also a lab scientist and it’s easy to for us to see our research solely in terms of the next publication. That is how our success and impact is measured in academia – and drives academic promotion. As a teacher and mentor of students and postdocs, though, I realize it’s very important to convey to them that medical research has to be clinically relevant.
As a postdoc at NCI, I was encouraged to try anything. A lot of it didn't work, but it was a great learning experience. When I became faculty, I had to apply for grants and I had to stick to things that were going to work to be funded. I didn't have the same freedom to explore new ideas. My BCRF award has helped to change that.
It all started with an unexpected discovery in the lab. We uncovered a very unusual protein that caused cells to die, but not through the usual processes. There was nothing in the scientific literature to explain what we found so I decided I was going to figure it out. Our results were so unusual, that nobody really believed them and I couldn’t get the research money I needed to do the work. Then, about five years ago, our lab identified the protein and I was able to get an NIH grant to start our current project. We named the protein CT20p and set out to understand how it works to kill cancer cells. Our BCRF project is a continuation of this NIH grant.
The experience made me realize how difficult it is to do exploratory research within the traditional funding structure. My BCRF award has given me the ability to return to my roots and pursue exploratory science again.
CT20p–Putting the brakes on tumor cell growth
The next breakthrough in the lab came when we discovered that CT20p regulates another protein called CCT. CCT is one of a family of proteins called chaperones. Chaperones play a very important part in protein regulation and can easily be overlooked as drug targets with all the focus on genes (DNA and RNA). When a protein is made (from the instructions from DNA), it is a single strand, or chain, of amino acids. Chaperones fold the protein so that in can interact with other cellular components to work properly. If a protein has errors in the way it folds, it may not function at all or may function in a very different way.
CCT is involved in the folding of several key proteins that become dysregulated in tumor cells, making it a very interesting target for cancer therapy.
We are currently working to understand how CCT works, why it works differently in cancer cells and what pathways are involved in upregulating it. Then, we want to understand how it functions in patients with cancer.
We began by looking at tumor gene expression in the TCGA database- a national repository of tumor gene mutations. We found that in 51 percent of breast cancer patients, the CCT gene was upregulated, regardless of hormone receptor status or other tumor biomarkers. We have seen similar things in advanced prostate, lung and liver cancers, as well as melanoma. These findings suggest that CCT overexpression is a unique feature of cancer cells, and I believe our research will ultimately show that CCT is a driver of cellular transformation. Because it functions at a very low level in normal cells, targeted therapy against CCT should have little effect on normal healthy cells, and we're hopeful that this will be particularly beneficial in metastatic breast cancers.
Understanding CCT to design better drugs
One of the first things we noticed when we treated cancer cells with CT20p in the lab was that they could not migrate, became unattached from the plate and caused tumors to liquefy, indicating that the tumor cells are losing their connectedness to each other. We believe this is through its action on CCT. Once the tumor cells become unattached they lose the signals they need to survive and subsequently die. It makes sense that these dying cells would then activate the part of the immune system that cleans up dead cells and lead to an immune response, much like a vaccine might. This is an area of study supported by our BCRF award.
We are also studying CCT amplification in different breast cancer subtypes, such as luminal or basal, to see if it is more frequent in certain types of breast cancer. Overall our BCRF funds are supporting two lines of research: The first question goes back to understanding what is unique about CCT in cancer cells, what types of cancer cells are most affected and how is CT20p interfering with its function? We'd like to use this information to identify which patients would benefit most from CCT-targeted therapy. The second component of our BCRF work is in immunotherapy. We want to confirm that by targeting CCT we can create an immunogenic response. Ultimately, we'd like to test the combination of immunotherapy drugs, such as the checkpoint inhibitors, with anti-CCT therapy.
At the AACR Annual meeting we presented work from our BCRF project that confirms that CCT is the target of CT20p, but we are also reporting that CT20p targets a very specific subunit of CCT. From this discovery, we further identified that this particular subunit called CCT2 is the portion of CCT that is up-regulated in breast cancer patients. We're in the process of performing high-throughput screening of potential inhibitors of CCT2, specifically.
Harnessing technology and building collaboration to move the science forward
Our lab is among the first to look at CCT in the context of cancer and we're creating the resources as we go. They don't exist because no one’s done work quite this way before. I have been very fortunate to have great people in my lab as well as great collaborators. One of our lab members is a biochemist, who developed the innovative protein folding assays that helped us to make the discoveries about CCT in breast cancer. A former student of mine is now one of my collaborators working out the protein structural assays that are allowing us to do in silico drug screening.
We’re also utilizing new technologies. We will use CRISPR gene-editing to delete the CCT gene to see how it affects response to CT20 and other anti-CCT agents. We are beginning to delve into studying circulating tumor cells (CTCs) from patient blood samples, so the liquid biopsy technology will be very important to our future work. My next step will be in finding collaborators in the stem cell field to help us to establish the molecular toolbox we need to study stem cells in patient samples.
All of these new toolkits come from collaborations with experts from different fields and that is what will help move our work and cancer research in general forward.
A future without fear of breast cancer
I see a bright future for breast cancer patients. Doctors and scientists are thinking about cancer treatments in the context of individual patients, as opposed to a one-size fits all approach. We don't have all the tools yet, but that kind of thinking is what is going to get us there. I am very optimistic that we are going to be able to substantially improve people's lives such that they live to die of something else and that we'll get there in a reasonable period of time. I get excited thinking about what we can achieve if we can make the big data accessible to all scientists and harnessing the information it holds. The challenges are to make the data accessible and interpretable and in training the research community how to use it.
If not for BCRF…
I love the way BCRF approaches science. We need the flexibility to adjust research aims based on new discoveries, as well as new technologies, and BCRF is the only funder that allows us to do that. Without BCRF, I would have eventually done what I wanted to do and perhaps made the same discoveries, but it would have taken so much longer.
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