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Promise and Progress - Bad Timing

Promise & Progress - A Spectrum of Achievements

Bad Timing

Date: January 15, 2015

Phuoc Tran
Phuoc Tran

Cancer cells are crafty—just ask clinician-scientist Phuoc Tran.  In his current research, he has seen how cancer co-opts an exquisite process of human development to undergo its most lethal transformation. This process, the one that 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 lung, prostate, liver, and bladder cancers.  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. 

Now, they can test drugs that could inhibit EMT and see the impact on all of the genes in its pathway.  If they can inhibit the gene, perhaps they can sensitize resistant cancers to radiation treatment and anticancer drugs. To test this, Tran is using the small animal model research platform (SARRP), a miniature radiosurgery machine where he can evaluate the effectiveness of potential drugs in a real radiation treatment environment and distinguish promising agents that warrant further studies from agents that do not work.

When Tran is not working on his EMT research, he is searching for other ways to sensitize cancers to radiation therapy.  He approaches the task like a detective, sleuthing out the unique instincts of the cancer cell.  Like any good investigator, Tran has created a profile of his villain. “Cancer is good at doing bad things, but it has certain things that it needs.  We need to figure out what these needs are and block them,” says Tran. 

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.

The next step, then, is to find a drug that blocks this gene.  He didn’t need to look far to find his answer—radiology and radiological science researcher Venu Raman, had already developed one. Tran is testing the effectiveness of the homegrown compound using his engineered mouse model and the SARRP.  Early promising data mean the drug may be moving closer to the clinic.

As a clinician and a laboratory scientist, Tran says he appreciates the value of basic science, but at the same time, he treats patients, some who are not doing well, and he recognizes the urgency of translating laboratory discoveries into patient care.  “It makes me impatient,” he says.  “I have a lot of optimism because of the unique tools and talent we have at the Kimmel Cancer Center.  I want to use this talent and these tools to get promising new therapies