Cancer cells are crafty—just ask clinician-scientist Phuoc Tran, M.D., Ph.D.. In his current research, he has seen how cancer co-opts an exquisite process of human development to undergo its most lethal transformation. A process that normally directs an embryo to grow from a single cell into a fully developed human being may be the same one used by cancer cells to invade other parts of the body.
This cellular guidance program is called EMT, and Tran says a cell undergoing EMT to form an embryo looks exactly the same as a rogue cancer cell as it spreads from its place of origin to a different organ in the body.
“The program isn’t bad, but the timing is,” explains Tran. The downstream consequences of this bad timing is the most critical event in the timeline of a cancer development, a sentinel event that often distinguishes a curable cancer from an incurable one. It is called metastasis, and it occurs when a cancer migrates to another part of the body. This is the stage that ups the ante, because it usually causes cancers to become resistant to treatment.
Stopping or reversing the event is a priority of Tran’s. “Local disease is often curable with standard therapies,” he says. “It is metastatic disease that patients are dying from, and deciphering EMT could be an important step toward helping these patients.”
EMT is a program that should be turned off and filed away after full embryo development. What reactivates it is not completely understood, but Tran suspects it is an ongoing injury to cells, such as chronic inflammation. “Cancer cells select the processes they need to survive. They don’t reinvent the wheel. Everything cancer needs is already there,” says Tran. “It pulls the programs it needs from our DNA and uses them to its advantage.” What’s more there is a natural cellular resistance built in to EMT. It’s an important safeguard that allows embryos to grow and survive, but in cancer, this resiliency makes for a resistant cancer. “A spreading cancer is like an astronaut going into space. He has special equipment to adapt and survive in a foreign environment. EMT provides survival gear to cancer cells allowing them to travel and invade distant parts of the body and resist external stimuli that would kill normal cells,” says Tran.
To prove his theory, Tran is using a uniquely engineered mouse model that allows him to turn genes on and off. By manipulating genes, he is able to make the mice get spontaneous tumors in different organs, creating an animal research model representative of the way humans develop cancers. With this realistic model, Tran can study the role of EMT in many cancer types. By incorporating luciferase, the gene in fireflies that causes their iconic glow, into the model Tran and team are able to make all of genes related to EMT glow in the mice.
He has identified a plant-based drug called harmine that directly interferes with the EMT program. Now, he can test the drug in his unique animal model and other laboratory models to see if can block EMT and convert resistant cancers to radiation treatment and anticancer drug-responsive cancers.
EMT is not Tran’s only focus, however. As a radiation oncologist, he is always searching for new ways to make cancers more sensitive to radiation therapy.
He believes he may have found one in the DDX3 gene. It is common across cancers, and if it is taken away, the cancer cannot survive.
Tran is collaborating with radiology and radiological science researcher Venu Raman, Ph.D., whose homegrown drug RK33 targets DDX3 and inhibits cancer cell growth and also their ability to repair DNA damage caused by radiation therapy. Tran is testing the effectiveness of the drug using his engineered mouse model and the Small Animal Radiation Research Platform, invented by radiation physicist John Wong. Early promising data mean the drug may be moving closer to the clinic.
The drug appears to have broad activity, already showing promise in sarcoma and lung, breast, prostate, brain and colon cancers. Tran says the next step is to gain investigational new drug approval from the FDA and funding to move the drug to clinical trials.