Dr. Annette Khaled and Her Latest Discovery, CT20

khaled_large featured imageOctober 22, 2014

With a Pegasus on the back wall of a mostly-empty conference room, and a well-spoken woman you might find yourself chatting with at the grocery store without realizing she’s on the forefront of the fight against cancer, what started as an introduction to her latest discovery, a peptide named CT20, became a testament to Dr. Annette Khaled’s experience throughout her career: that the unexpected is actually the more interesting result.

She’s found that to be the case as a researcher, and it’s evident in every twist and turn of the story behind CT20 and its future promise as a treatment for patients with cancer.

One of the first hires in the early days of UCF’s biomedical program now featured in Lake Nona as an integral part of the medical city, Khaled was attracted to the university because of the chance to make her mark. As the biomedical program has grown to become a home to dozens more professors, she’s been able to be a part of the growth as it developed and to form partnerships within the university by collaborating with researchers in fields like nanoscience and biophysics.

An immunologist, Khaled traces the beginning of her story with CT20 back to an illustration of her experiences with research that doesn’t go according to plan. Her work has often focused on a particular protein, a death protein, named BAX.  When activated, the protein is responsible for mediating the death of cells—every cell has it, and when it’s time for a cell to die, the protein helps the cell die. She followed up her deceptively simple explanation with the question people have been asking about BAX since its discovery. How does a protein that sits inside a cell for its whole life, doing nothing, become activated when it’s a cell’s time to die?

Khaled conducted an experiment during her time at the National Cancer Institute in Maryland at the beginning of her career, an experiment to study how a change in cell pH, where cells become more acidic before they die, could be related to what activates BAX.

After conducting the experiment, she recalls going to her boss at the time, saying “Well, you know… it didn’t really work. It didn’t really change much. Here’s my data.” Seeing a surprise, he pointed to the beginning of the experiment, to data she’d recorded over an extended period of time for good measure. While both researchers expected dying cells to show increased acidity in their final moments, Khaled had accidentally discovered a period before that, one of alkalinization—the opposite.

With a long time course for the experiment, chosen just to be thorough, Khaled had found a connection between cell alkalinization and the activation of the death protein that held promise as a key to developing treatments for cancer and neurodegenerative disease. The discovery became one of her major publications in post-doctoral research, and set the stage for a career chasing the unexpected.

“There’s a lot more to study and discover, but that’s why we love science,” she mentions as a takeaway from the unexpected result.

Funding from the National Institute for Health in 2008 gave a green light for Khaled’s more recent research into BAX and its important role. BAX is like a Slinky, she says.

She explains that the protein is composed of sections in a helix shape. Khaled and her research team separated these in order to study the last little helix, the final curve if the protein were a Slinky. Thinking its role was to attach the protein to cell membranes to help the cell die, they attached this little helix to a fluorescent protein to watch how it worked. But instead of moving from point A to point B, the little helix killed the cell.

Khaled remembers thinking “That ends my work. I can’t proceed any further; all of the work I was planning to do was based on being able to study the movement that this helix caused.”

“By killing the cell, it was like ‘Well, that’s the end of the project.’”

Momentarily directionless, she considered how to move forward when what she and her team were going to study and develop, the protein’s hypothesized movement, was now cell death. It’s at this point she brings up the lesson she wishes more people understood about research. The unexpected is actually the more interesting result.

She considered that they could study the little helix by itself, recalling her thoughts of “Forget BAX! Forget this other protein we were studying! Let’s study why this helix kills. Maybe there’s a way to use this therapeutically.”

Changing the direction of the lab, Khaled studied this small helix within BAX—figuring out how it works, what its target was, how it killed, and what it did to cells. Today, she’s adapting this mechanism therapeutically in the form of CT20 so it can be used to treat patients who have terminal diseases, adding, “Five years later… we actually sort of mostly figured it out, I think.”

. . .

A quick read of the papers filed through the UCF Office of Technology Transfer to patent her new discovery, the CT20 peptide, reveals a disconnect (at least to one not well-versed in biomedical science) between the story so far about sudden cell death and the peptide’s mechanism of preventing cells from moving.

I ask her how the two are related and she begins explaining that cells need to contact each other to survive. A cell in isolation will die; a cell will need to contact another cell or something in the environment it’s in because it needs to receive stimuli from its environment. She goes on to say, “So cancer cells for example…”

My curiosity gets the better of me and I interrupt: “It gets bored to death?”

“Yeah, it does!” she exclaims. “It basically gets bored, so a cancer cell especially has to be able to go attach itself and grow in a location and separate itself to go to a new location, for example the brain or the lungs, and regrow.” She explains how a cell’s ability to sample its environment and attach, detach, to “make new friends” is critical for cancer cells especially.

CT20 interferes with the ability of a cell to be flexible. In order to move around in our daily lives, we need the structure of our skeleton, and a cell requires the same of its cytoskeleton. It has to extend part of itself to be able to attach to any location, which it does by rearranging the cytoskeleton. CT20 interferes with the structure of the cytoskeleton, breaking it down within the cell that now can’t move, can’t reach out with its extensions, called pseudopodia, and can’t attach to anything.

“They die from loneliness, if you want to think of it that way,” she continues. “They lose the ability to be able to attach to anything, to bind to anything, and after a short period of time they will die.”

My mind races through the terrible consequences of what would happen if every cell in a body did this. She goes on to say, “So we’re talking about cancer cells, and that’s what’s really cool. A normal cell isn’t affected this way. The peptide goes into a normal cell, and nothing really happens. It targets cancer cells specifically, and the weakness in cancer cells.”

This is what makes CT20 a breakthrough and a step beyond what’s currently available to fight cancer. Most drugs, she explains, including chemotherapeutic drugs, target many cells—they’re not just going to kill your tumor cells, they’re going to kill any other cell in your body. When it comes to other drugs that do target cancer cells, the problem is that they’re killing the cells that are actively dividing.

I’m caught off-guard by this, but by now I’ve learned to wait for her to drop new knowledge and she doesn’t disappoint. “That’s actually wrong,” she says, “cancer cells don’t actively divide.”

“As a matter of fact, we’re learning that the real cells that we need to target in cancers are not the cells that are dividing, but the parent cell, the cell that gave rise to that tumor in the first place. Those don’t divide.”

What researchers are now figuring out is that the state-of-the-art treatments developed over the course of many years are killing off the wrong cells. Though the treatments may reduce a tumor’s size, making surgical removal an option, they’re not getting to the true cells, the stem cells, that gave rise to the tumor.

“And so we have to develop a whole new arsenal of drugs, basically, with our better understanding of what the tumors are, that will target those cells. That’s what CT20 does.”

CT20’s ability to kill off the parent cells that give rise to the cancer cells, or kill off the cells that have matured in a way and travel to other parts of the body, makes it a forerunner in a new generation of more targeted drugs that kill the cancer cells that need to be killed while not affecting normal tissue.

For patients, this difference is tremendous.  With traditional cancer treatments, the strength needed to kill cancer cells also kills other cells without discretion. In contrast, “We don’t know the side effects that CT20 can cause,” Dr. Khaled says, “but at this point, we haven’t seen any within the lab or with mice.”

To clarify her hopefulness, she talks about a time when a researcher in her lab accidentally injected a mouse in its kidney instead of its tumor, leading Khaled to worry for the mouse’s life before delightedly finding that the mouse was perfectly fine—CT20 left its normal tissue alone, as it might in human patients.

Before CT20 can be used as a treatment, more research is needed to develop a delivery method for the peptide. Khaled and her team were recently funded to develop a delivery platform to put the peptide within and give to a patient as a drug: a way that zeroes in on tumors or on migrating cells that have left and are traveling around the body.

The next step is a big one. “Right now, you know, a patient comes to me and says ‘I want your peptide; I want to be treated with your peptide,’” she says, “and I don’t have a way to deliver it.”

While still in a stage of development, CT20 holds promise as more than just a potential treatment for patients. By understanding its target and what the peptide attaches to when it enters a cell, the discovery has opened a new area of research as a new biomarker.

“Now that we understand what the Achilles’ heel is, basically, of these cancer cells—what makes these cancer cells die when they’re treated with our peptide, how it disrupts their cytoskeleton—we’ve actually identified a new protein that can be used as a biomarker, maybe for detecting cancer, which is another problem. A person has cancer, the cancer’s cured, and twenty years later the cancer comes back. How do you know it was going to come back? How can you monitor that patient to find out if the cancer’s now returning? There’s nothing to use and usually by the time it happens it’s too late. So you can develop this biomarker that would actually help you figure this out—that would be really powerful,” she explains.

While excited about the prospects of the CT20 peptide, Dr. Annette Khaled is passionate about another cause: getting the word out about what the research process is really like. She notes that people seem to think new innovations just magically appear, when it’s really the result of day-to-day lab work that can feel like drudgery.

“You do ten experiments and you’re lucky if one worked. I’m telling you a complete story,” she says to me, “but you didn’t see the five years of mistakes. Well, not mistakes… you know, wrong tracks, wrong ideas, or experiments that didn’t work the way they were expected to, where we had to redo them. All of those to finally lead to the truth, to discovering the truth, is really a very, very complicated process. And I just wish people understood that. They always see the end result, but you don’t see the effort and the time and the number of people that put their years into figuring this out. So I guess that’s the point I kind of wanted to make. It’s a cool story, where we are right now. It has great potential for the future, but it’s a lot of hard work that people put in to get to this point.”

Sorry, Blake Bortles. I have a new favorite celebrity Knight now.



The recent grant from the National Institute of Health was received based on Dr. Khaled’s collaboration with Dr. J. Manuel Perez, who is credited with developing the delivery system for the CT20 peptide.


By Lisa Bottomley