Blocking Cancer-Causing Proteins
Using a method that starts with virtual computer modeling, Cincinnati Children's researcher Yi Zheng, PhD, and his co-workers design lead drugs that block overactive cancer-causing proteins and help chase cancer cells out of their hiding places in the body. "Our lab figures out which proteins are signalling too much, and what we can do to return them to normal," said Zheng. "Turns out, if you can return the signalling to normal, you can freeze transformation (switching from a regular to cancerous cell) and make the cancer cells less invasive."
One drug candidate that Zheng has already licensed to a pharmaceutical company blocks a protein called Rac, that can malfunction and send too many chemical signals to other proteins in the cell. The drug candidate is called NSC23766, and it is considered a "lead" drug because it works against leukemia, lymphoma, prostate cancer and lung cancer in mice—killing a significant percentage of cancer cells and delaying cancer onset—but it still needs to be tested in humans.
Other drugs that Zheng is developing might be able to chase cancer cells out of hiding places in the body called niches, and this could be the key to making cancer curable. A niche harbors a particular type of cancer cell, and the conditions in that niche protect the cancer cell from being killed by traditional methods. For example, chemotherapy might not get to leukemia cells hiding in the bone marrow. "The hypothesis is that cells hiding in their niche repopulate after chemotherapy and cause the cancer again," he said. "That's why instead of a cure, people often talk about two-year, five-year, or ten-year survival."
Zheng hopes to solve the niche problem by blocking Rac and its relatives (which are all part of what's called the "Rho-GTPase" family). They play a large role not only in cell signalling, they also regulate cell adhesion. If Zheng's drugs can prevent cells from sticking to other cells, he might be able push cancer cells out of their niche. "By targeting Rho-GTPase, the cells loosen up, blood moves, the leukemia cells might be pushed out of the bone marrow," he said. Once a cell leaves its niche, conventional chemotherapy can kill it and eradicate the cancer for good. There could be a chance to cure the cancer rather than just stave it off.
To target Rho-GTPases, Zheng starts by modeling millions of molecules on the computer to see if the shapes fit into the target he hopes to block, like puzzle pieces. "We know the structure of our target molecule, and how it is activated," he said. "Then we use computer-based virtual screening to match millions of compounds to see if any fit. If one molecule fits into the right spot, like a glove, then it goes on the short list."
The short list of about 50 molecules is then tested physically in the lab to see if they bind in real life like they did on the computer screen. "We try to reveal so-called crystal structures with x-ray crystography (a method for viewing the real 3-D shape of the molecule locked into the protein)." Based on the structure, the lead drug can be modified to look more like a real drug. Zheng also tests the efficacy of the molecule in a real cell, and then in an animal. "Here you also need luck, because not all compounds will be able to enter the cell and act as they do in a test tube," he said.
In addition to NSC23766, which has already passed these tests, Zheng and his colleagues are currently working to achieve a crystal structure for a Rho inhibitor that looks promising based on cellular tests. "We carry out the pre-clinical work in my lab," he said. "After that, we hope to collaborate with pharmaceutical companies and clinical researchers to develop it into trials in humans."
