Cerione_Streched.jpg

“We’re trying to understand what allows a cancer cell to be a cancer cell.” “We’re trying to understand what allows a cancer cell to be a cancer cell.”
Beatrice Jin
Beatrice Jin

11_20_14_Rick Cerione_0036.jpg

Cerione says his greatest goal is to fulfill the cliché—going from a molecule in the lab to the bedside. Cerione says his greatest goal is to fulfill the cliché—going from a molecule in the lab to the bedside.
Frank DiMeo
Frank DiMeo

11_20_14_Rick Cerione_0054.jpg

The lab’s primary focus is cell metabolism, which changes wildly when a cell goes from normal to cancerous. The lab’s primary focus is cell metabolism, which changes wildly when a cell goes from normal to cancerous.
Frank DiMeo
Frank DiMeo

11_20_14_Rick Cerione_0044.jpg

To successfully get the drugs Cerione’s lab helped develop into patients would be a great achievement for them.” To successfully get the drugs Cerione’s lab helped develop into patients would be a great achievement for them.”
Frank DiMeo
Frank DiMeo

The Fight for Better Cancer Drugs

by Lauren Cahoon Roberts

Could one tiny enzyme be the key to cancer’s defeat? Richard A. Cerione, Chemistry and Chemical Biology/Molecular Medicine, is trying to find out. By studying the metabolic pathways that keep healthy cells on track and let cancer cells run wild, Cerione may be closing in on some promising new candidates for therapeutic targets.

Like many cancer researchers, Cerione has personal experiences that motivated him to work in this field. While finishing his PhD, his grandfather, who had spent a great deal of time with him as a boy, passed away from pancreatic cancer. Later, while doing postdoctoral research in biochemistry at Duke University with Robert Lefkowitz, the 2012 co-winner of the Nobel Prize in Chemistry, Cerione walked through the children’s ward of a cancer center. “At that time, my focus was more mechanistic and molecular than biomedical,” says Cerione. “But I was totally struck by that experience in the children’s ward—the parents looked worse than the kids. It stayed with me.”

Since then, Cerione has been driven to use his knowledge of biochemistry and cell biology to find tangible results for cancer patients. “We’re trying to understand what allows a cancer cell to be a cancer cell,” he says. His primary focus has been on cell metabolism, which changes wildly when a cell changes from normal to cancerous.

The Metabolic Machinery behind the Scene

In healthy cells, two key cycles provide them with energy: glycolysis and the citric acid cycle. Glycolysis occurs in sugar molecules, converting them into the intermediate compound pyruvate. This compound serves as fuel for the second cycle—the citric acid cycle—which produces adenosine triphosphate, or ATP, the primary energy molecule that powers all cells and keeps the metabolic machinery humming.

In cancer cells, however, this coupling of the two cycles is disrupted. The phenomenon, known as the Warburg effect, was observed nearly a hundred years ago by Nobel laureate Otto Heinrich Warburg and has proved to be a key in Cerione’s work. This uncoupling “presents a dilemma for cancer cells,” says Cerione. “They’ve lost that input from glycolysis. So they compensate by using glutamate (instead of pyruvate) to feed their citric acid cycles.”

To do this, the cancer cells rely heavily on an enzyme known as glutaminase to turn glutamine, an amino acid that’s abundant in the cellular fluid, into their newly scrounged-up fuel glutamate. The enzyme typically shows little activity in normal cells, whose well-coupled metabolic cycles have little need for high levels of glutamine metabolism—but cancer cells are in “desperate need” of the enzyme.

Cerione’s lab came upon the importance of glutamine metabolism while searching for specific inhibitors that would block the ability of Rho GTPases, signaling proteins that act like molecular switches in cells to help drive malignant transformation. The specific inhibitor they found did not act directly on Rho GTPases, but instead blocked signals from these GTPases that increased the expression and activation of glutaminase. This behavior presented Cerione with a sort of Achilles' heel that could be exploited. “What we like to say we’re doing is that we’re starving the cancer cells,” says Cerione. “The trick is to get a specific inhibitor that just inhibits that pathway in cancer cells, and nothing else.”

Because normal cells barely use glutaminase, there’s a good chance that targeting this enzyme would present an improved method of fighting cancer. Currently, most therapies kill cells indiscriminately, taking out healthy cells along with the cancerous ones, which leads to serious and sometimes insurmountable side effects.

Cerione is driven to use his knowledge of biochemistry and cell biology to find tangible results for cancer patients.

Cerione and his colleagues are currently testing glutaminase inhibitors in mice that contain human breast cancer tumors, using a system that was originally developed by their collaborator, Alana Welm, while she was at the Huntsman Cancer Institute in Utah. These mouse tumor grafts show the same characteristics as the original tumors in patients. So far, the results have been very exciting. The Cerione group is finding that metabolic inhibitors of glutaminase are quite effective in blocking tumor growth in mice.

Doubling the Approach

Cerione is exploring not only how to exploit the internal weakness of cancer cells but also how to attack them at their surface. Another defining feature of cancer cells is the presence of microvesicles, which are small pods containing specific proteins and RNA that coat the outer membrane of the cell. “When a cell becomes cancerous, one of the outcomes of the metabolic changes they undergo is the production of these microvesicles, causing the cancer cells to become absolutely covered with them,” Cerione explains. “Cancer cells shed these vesicles, particularly as they become more aggressive, and we’ve discovered that they can spread to normal cells and cause them to become cancerous in turn. So, if we can disrupt the function of microvesicles, we can go a long way toward stopping tumor growth.” One approach is to use the metabolic inhibitors the lab is developing, as they offer the possibility of a "double-bang for the buck" by blocking the metabolic activities required by tumor cells and inhibiting their ability to generate microvesicles.

Collaborating for Translational Results

Cancer cell microvesicles are also catching the interest of pharmaceutical companies, which view them as potential biomarkers for distinguishing between normal and unhealthy cells, making them a useful diagnostic tool.

Cerione’s group has recently partnered with oncologist David Nanus at Weill Cornell Medicine who is treating kidney cancer patients. Cerione hopes to improve their treatments by exploring if microvesicles act as an effective biomarker for the disease.

“My greatest goal would be to see if we can actually fulfill that old cliché—going from a molecule in the lab to the bedside,” says Cerione. “It would be a great achievement to get these drugs we helped develop into patients and see them be successful.”