Eisenman receives $7M NCI Outstanding Investigator Award

Molecular biologist will continue to seek tumors’ weaknesses by mapping important molecular pathways
Dr. Robert Eisenman
Dr. Robert Eisenman received an NCI Outstanding Investigator Award to seek out tumor cells' hidden weaknesses. Photo by Robert Hood / Fred Hutch News Service

Dr. Bob Eisenman, a molecular biologist at Fred Hutchinson Cancer Research Center, has received an Outstanding Investigator Award from the National Cancer Institute. The award is given to investigators pursuing projects of “unusual potential” in cancer research. Eisenman studies a specific family of molecules that turn on cellular growth genes. He has spent decades disentangling the network of genes regulated by this group of molecules in an effort to understand how cancer cells co-opt these molecules and the gene networks they orchestrate.

He will use the Outstanding Investigator Award, which provides $7 million over seven years, to learn even more about these pathways, how to inhibit them and halt cancer growth.

“It’s exciting for us to be recognized,” Eisenman said. “The award really allows us to build on our ongoing research in a very productive way. It gives us the wherewithal to carry the work into new directions. We can be more fearless.”

Charting molecular pathways to find tumors’ vulnerabilities

Molecules that turn genes on are known as transcription factors. Eisenman works on a specific group of related transcription factors known as the Myc family. Normally, Myc transcription factors orchestrate a host of genes that control cell growth. Cancer cells find ways to shove cellular growth into overdrive by throwing Myc activity into high gear.

“Essentially, the questions we try to answer are, ‘What kind of molecular machines are these transcription factors? And how does that machinery work?’” Eisenman said.

He has been studying how normal cells turn cancerous since his days as a postdoctoral fellow.  Since the early 1980s, Eisenman has worked to untangle how cancer cells take advantage of Myc’s usual functions and to discover the other molecules that coordinate with or oppose Myc’s activity.

In his Outstanding Investigator Award, Eisenman proposes three main research directions based on this foundation. One project will focus on a change in the DNA sequence of the Myc gene. Strikingly, most tumors find ways to ramp up Myc activity without modifying its DNA sequence. This single, specific mutation is the rare exception. Eisenman’s team has shown that it results in altered activity and stability for the Myc protein. In a mouse model his group developed, this change gives rise to a plethora of blood cancers, and Eisenman wants to understand why.

“By concentrating on this single mutation and what its consequences are, we think we can really learn some of the basic aspects of how Myc works,” he said.

In the second project, Eisenman will concentrate on an enormous protein called Mga (pronounced “mega”), which his team discovered over 20 years ago. Mga interacts with the network of proteins made up of Myc and its molecular partners and is often inactivated or turned off in cancer.

“That got us extremely excited about what its function might be,” Eisenman said. The fact that Mga is often shut off in cancer suggested that Mga might counteract Myc’s tumor-promoting qualities — but how?

Comprised of some 3,000 amino acids, Mga is about five times larger than most proteins that molecular biologists study, and for years the leading gene-manipulating technology was no match for this monstrous molecule. But now Eisenman and his team have CRISPR, the precise new DNA-editing technique, at their disposal. Using CRISPR, they collaborated with Hutch colleague Dr. David MacPherson to inactivate Mga in a mouse model and have begun to learn how it may work against tumor formation in normal cells.

For the third project, Eisenman will investigate a protein called MondoA, which could be Myc’s Achilles heel. As it happens, cells aren’t well equipped to handle the out-of-control production of proteins, membranes and new energy sources that are required for out-of-control growth.

“If you’re going to be a tumor, you need to really grow,” Eisenman explained. “Myc pushes cells to do this, but the consequence is that it stresses the cells.”

Too much cellular stress is deadly. MondoA calms down Myc-stressed cells. With MondoA’s help, they can overgrow without a fatal breakdown. Because of this, MondoA is critical for keeping frenetically growing cancer cells alive. Eisenman has found that in cancer cells that rely on Myc to drive growth, loss of MondoA slows that growth. This means that MondoA, or the pathways it orchestrates with Myc, could be potential therapeutic targets. Now, Eisenman proposes to continue untangling this interaction and extend the work to a variety of tumor types.

“All of these projects involve functional pathways for genes that are important in cancer. The overarching goal is by understanding those pathways, we can discover how to inhibit them,” he said.

Read more about Fred Hutch achievements and accolades.

Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.

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