We all fear cancer. It feels like a death penalty when hearing the diagnosis.
Cancer chemotherapy brings additional hope of survival, but it often adds another layer of fear because of side effects such as hair loss, nausea, and weakness. Cancer chemotherapy treatment is advancing, but this difficult research is still in early stages. Currently, many types of cancer chemotherapy are very toxic because the treatment kills normal cells as well as cancer cells, limiting effectiveness and increasing patient discomfort.
My research lab is studying a specific protein called survivin, which holds some promise for selective cancer cell killing. Researchers have previously discovered that survivin is essential in early embryo development. We now know that survivin prevents cells from dying and allows them to keep dividing and making all the required organ structures for the embryo to grow and survive independently. Once embryonic growth and organ formation is done, survivin is present at much lower levels in cells.
In adults, normal cells stop growing once they form a functional organ. If something goes wrong, survivin has been reported to help cells repair themselves, or if they cannot, the damaged cells then enter a programmed cell death pathway to avoid buildup of errors. But we have found that survivin also helps survival of cancer cells.
Many cancer cells in adults have high levels of survivin, as if they have returned to the embryonic stage. Despite high levels of survivin, cancer cells are not able to fix errors, but survivin does allow cancer cells to keep dividing with increasing errors.
If we can lower survivin levels in cancer cells, we can slow down cancer cell growth. How can we do this?
We have discovered, by careful investigation at the molecular level, that survivin is stabilized by forming a dimer of two survivin proteins wedged together. We also discovered that if we can put a small molecular wedge between the two survivin proteins, they will break apart. Once a survivin dimer is wedged open, it gets degraded within the cell.
Researchers now have the ability to design specific molecular wedges, called small molecule inhibitors. A well-designed inhibitor can only bind to a specific structure, much like a key fitting only a certain lock, or binding only to a survivin dimer but not to other protein dimers. This feature makes the small molecule inhibitor more targeted, therefore with fewer side effects.
After testing hundreds of thousands of key-and-lock combinations using computer modeling, we have found a few that can wedge open the survivin dimer. Now, we are testing these small molecule inhibitors for accuracy and effectiveness in actual cancer cells. But because both survivin and the small molecule inhibitors are not visible, even with a microscope, we needed a tool that measures the effect of the small molecule inhibitors specifically on survivin dimers.
Researchers are now able to add different molecular signals at specific locations on individual proteins. Using this knowledge, we put a molecular light on one survivin protein and a light switch on the other. If they are close enough to form a dimer, the survivin with the light switch turns on the molecular light on the other survivin, and this survivin dimer lights up. By measuring the amount of light produced, we can then tell the number of survivin dimers. We next tested our small molecule inhibitors on these survivin dimers that light up.
Interestingly, some of our small molecule inhibitors fit the keyhole but did not wedge open the survivin dimer, but other small molecule inhibitors were able to wedge open the survivin dimers and switch off the light.
Finally, we tested the small molecular inhibitors that opened the dimers within cancer cells. The cancer cells exposed to the effective molecular inhibitors stopped growing and died, which is very promising, but still far from clinical use.
Our future goal is to make even better small molecule inhibitors for treating cancer. For example, we are working on making small molecule inhibitors even more specific to survivin dimers and wedge them open more quickly. Some new molecular tools may also help direct inhibitors only to cancer cells, leaving normal cells with survivin dimers unaffected by the inhibitors.
Our research lab is working hard to make small molecule inhibitors that produce mild side effects, shorter treatment time, and less cost, and, ultimately, to make cancer a less horrifying word.
Jackson Huang is a Ph.D. student in the cell and cancer biology track in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. Jackson is conducting his research in the laboratory of Dr. Jian-Ting Zhang. For more information, contact Caoqinglong.Huang@rockets.utoledo.edu or go to utoledo.edu/med/grad/biomedical.
First Published June 6, 2022, 12:00 p.m.
