Uncovering cancer’s metabolic quirks

Hutch News

Uncovering cancer’s metabolic quirks

Study reveals how many tumors fuel their rapid growth, suggesting possible new drug targets

Feb. 11, 2015
Fred Hutch researcher Dr. Robert Eisenman

Fred Hutch researcher Dr. Robert Eisenman published a paper this week identifying a protein necessary for the growth of many types of cancer. That protein, MondoA, may become a promising new drug target.

Photo by Bo Jungmayer / Fred Hutch News Service

A new study has revealed why many cancers grow so rapidly, pointing to a possible Achilles’ heel that could be exploited in new cancer treatments.

That weakness is in how cancer changes cell metabolism, hijacking normal cellular processes to crank out a massive store of raw materials to support its rampant growth.

The study, which was published this week in the journal Cancer Cell, identifies a protein called MondoA which is necessary for cancer’s growth spurt and could be a promising drug target, said Dr. Robert Eisenman, a basic science researcher at Fred Hutchinson Cancer Research Center whose laboratory team carried out the study.

Their findings suggest that MondoA plays a role in cancers that are driven by mutations in the oncogene known as Myc. At least half of all cancers are driven by mutated Myc, including leukemias, lymphomas, and lung, breast, brain and ovarian cancers.

In healthy tissues, the Myc protein is a central player in cellular metabolism. Normally Myc’s activity is held in tight control by several checkpoints, all of which act together to make sure cells grow just enough – but not too much. But when Myc mutates in a certain way, it casts off those cellular shackles.

With those cancer-driving mutations, Eisenman said, “it’s as if [Myc] has a foot glued to the gas pedal.”

In healthy cells, Myc is part of a balancing act that routes glucose into separate processes that convert the cellular fuel into either energy or building blocks to construct new cells. In cancer, that balance swings toward creating material for new cells to support tumors’ rapid growth.

‘If we understand it, we can fix it’

Because Myc is intertwined with so many fundamental aspects of cellular growth, researchers have been unable to develop Myc-specific cancer drugs that could kill tumors without harming a significant number of healthy cells. So Eisenman and his team set out to find other proteins that help Myc commandeer cells’ metabolism, proteins that could potentially serve as novel drug targets.

His team found that Myc relies on MondoA to keep cancer cells alive. MondoA relays information about glucose availability to the cancer cells and helps adjust the cells’ metabolism to the needs of the tumor. Eisenman’s team found that when MondoA is missing the cancer cells become stressed to the breaking point.

The researchers tested the role of the two proteins by seeding mice with human neuroblastomas, a common type of cancer in children and which is driven by Myc mutations. When the researchers shut off MondoA activity in these tumors, they barely grew at all.

“If we look inside these tumors, we find that they’re dying,” Eisenman said.

Aiming drugs at MondoA in the hopes of improving treatments for cancers driven by mutated Myc is feasible, Eisenman said. Some drugs already exist that inhibit the metabolic events controlled by MondoA. He hopes his group’s findings will spur others in the field to test those drugs for their potential to treat cancer.

Although the human impact of his findings are likely years away, Eisenman is pleased that the decades he’s spent studying Myc and all its mysteries are finally bearing fruit.

“We’ve learned a lot about Myc’s function and what it does, and now we’re in a position to understand what its real role in tumors actually is,” he said. “If we understand it, we can fix it.”

Dr. Rachel Tompa, a staff writer at Fred Hutchinson Cancer Research Center, joined Fred Hutch in 2009 as an editor working with infectious disease researchers and has since written about topics ranging from nanotechnology to global health. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Reach her at rtompa@fredhutch.org.

 

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