Stopping Colon Cancer by Targeting a Protein “Turned on” by Mistake

Nan Gao, PhD
Institution: Rutgers, The State University-Newark Campus
Area of Focus: Tumor Biochemistry and Endocrinology
Grant Term: 7/1/2015 to 6/30/2019

The Challenge: Most colorectal cancer (CRC) cells have a change (mutation) in one of two genes—the APC gene or the beta-catenin gene. Research suggests that after the gene mutates, the very first tumor cells can become hypermutated, meaning they develop more mutations, get stronger, and can survive better.

When this happens, the cancer eventually spreads far from where it first started, advancing to a late-stage cancer that’s hard to treat. A better understanding of how CRC cells progress from having only one mutation to having many mutations could help lead to new treatments.

The Research: Nan Gao, PhD, and his team want to find a way to stop those early tumors with only one mutation from getting stronger and having multiple mutations. One suspect is a protein that acts like a switch, called Cdc42-v2. When this protein is “turned on,” it helps tumors grow. If Gao and his team can find a way to “turn off” this protein, they could limit the cancer’s progression and spread.

Cdc42-v2 is normally found in the brain, but this “switch” can get “turned on” by mistake in CRC cells in the intestines. Gao and his team thought that finding out how this protein works in mice could help scientists develop treatments to kill CRC in the early stage.

CRC can be triggered by repeated injuries to the lining of the intestines. Gao’s team discovered that the injured lining of a mouse’s intestine can be changed back to its earlier phase, called a cancer stem cell. These cells divide more slowly and don’t respond well to the drugs that kill 99% of the more rapidly dividing cancer cells. It they’re not stopped, they can “re-seed" the cancer.

He found that these intestinal cancer stem cells in mice need Cdc42-v2 to grow. Removing or “turning off” Cdc42-v2 stops tumor growth. Gao also discovered another group of proteins (called GTPase) that can stop CRC from growing.  

Why Does It Matter? The researchers hope what they learned about Cdc42-v2 will someday translate into treatments that target the protein. If that happens, such treatments could help stop CRC before it really gets started.