Collaboration leads to new pathway to increase drug sensitivity

October 19, 2016 | by Katie Neith

 

Kong-Mei Mei Kong, Ph.D.

 

Science doesn’t always start in the lab. Sometimes collaborations come together over cocktails in Costa Rica.

This is how City of Hope cancer biologist Mei Kong, Ph.D., and California Institute of Technology (Caltech) neuroscientist Viviana Gradinaru, Ph.D., met as Pew scholars at their annual retreat. Soon after they started a project - with the help of the Caltech and City of Hope Biomedical Research Initiative - that could change the approach to killing cancerous tumors.

Gradinaru, assistant professor of biology and biological engineering and Heritage Principal Investigator at Caltech, said many ideas are often discussed in social settings at conferences but never move forward. “We go back to … the noise in our usual daily business, and we forget if the right catalyst is not there,” she said at the “Partners in Innovation,” a symposium given by Caltech and City of Hope last month. “[But] Dr. Arlene Chiu was there and the City of Hope-Caltech program was there to actually get us started.”

Kong and Gradinaru were at the symposium - which was developed by Chiu, who earned her Ph.D. at Caltech and is director of the Office of New Research Initiatives at City of Hope - to present the latest findings of their research together. Through joint studies, they have found potential new ways to increase drug sensitivities in tumors.

“We are interested in studying how cancer cells deal with hunger so eventually we can target this pathway to starve cancer cells,” explained Kong, who is an associate professor in the Department of Cancer Biology at Beckman Research Institute of City of Hope.

One nutrient that supports tumor growth is glutamine — an amino acid popular with athletes for its energy-producing qualities. But cancer cells at the core of a tumor, which are also the hardest to kill, are unlikely to have much access to glutamine and other nutrients. Given this knowledge, Kong said she and her team arrived at a “very scary hypothesis: under low-glutamine conditions, some of the cells not only survive, but they convert themselves to super cells with drug resistance.”

In order to test this theory, Kong sought to look inside tumors using a technique previously developed by Gradinaru to render opaque tissues, such as the brain, completely transparent (a process called tissue clearing) while chemically labeling particular cells in order to create 3-D models of organs, bones and even tumors. Traditionally, seeing inside a tumor would involve timely, labor-intensive tissue slicing and tumor reconstruction that is prone to error. But Gradinaru’s Passive CLARITY Technology (PACT) gives a picture of the whole tumor for accurate comparison within tissue.

Gradinaru applied PACT to melanoma tumors, which have very low glutamine in the tumor core, clinically are very hard to treat and often become drug resistant. Kong then stained the tumor and was able to see increased gene regulation in the core but not in periphery, indicating that changes in gene expression may contribute to drug response in the tumor core.

“We demonstrated that the increase in gene regulation that we see in the core has mainly resulted from a decreased glutamine level,” said Kong.

Additional tests also proved that the decrease in glutamine level led to drug resistance. Next, the team found a way to block the pathway for gene regulation in order to convert the core cells into drug sensitive targets. When they combined the blocking agents with current melanoma treatments, tumor growth dramatically decreased.

“This collaboration with Viviana allowed us to test, for the first time, whether the nutritional microenvironment within a solid tumor could affect drug response by directly monitoring the whole tumor,” said Kong. “Also I believe this collaboration provided a very important molecular basis to use combination of therapy to increase drug sensitivity.”

The team’s work was recently published online in Nature Cell Biology.

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