Shining a Light on protein-to-protein Interactions in Cancer

A decade ago, pharmaceutical researchers drew a circle in the sand of the human genome, declaring what was inside was druggable. The idea was to focus on the types of genes and proteins that scientists know from experience how to target.

One consequence was that the rest of the genome, most of it, was designated as too difficult to reach. The idea established a psychological barrier, creating a situation akin to the drunken man looking for his keys under a lamppost, instead of where he dropped them, because "the light is better."

In cancer, many of the genes that are the most important drivers of tumors growth are, by this analogy, in the dark. Emory pharmacologist Haian Fu wants to bring them into the light with an innovative approach to finding new anticancer therapies. He is backed by a five-year, $4.2 million grant to Emory from the National Cancer Institute to establish the Molecular Interaction Center for Functional Genomics (MicFG).

"Every time I talk about it, I get excited," Fu says.

To understand why he is excited requires another look at the druggable/undruggable distinction. Scientists consider some proteins as druggable because they belong to certain families of enzymes. Chemists can envision how to stick a drug into the active site of the enzyme and disable it. Other proteins also make good targets because they exist outside of the cell, so antibodies can be engineered to grab them.

But many of the proteins that appear to have critical roles in cancer cell growth are conventionally considered undruggable. Why? Some bind to DNA directly and turn on genes. Others are important building blocks inside the cell. Chemists regard these proteins as challenging because a drug would have to stop the protein from nestling against its partners, and there are no active sites to target, just broad surfaces.

With the aid of robots, scientists at Emory’s new cancer genomics center will create intricate maps of protein-to-protein interactions (PPI) to document how they are altered in brain, lung, and breast cancer cells. The center will share expertise with the existing Emory Chemical Biology Discovery Center, also led by Fu, which uses robot technology to sort through thousands of chemicals for potential drugs. At the MicFG, the task focuses on identifying the most strategically important points on the PPI maps.

Advanced DNA sequencing technology now makes it possible to read the entire genomes of individual patients’ tumors, and Emory’s Winship Cancer Institute has been participating in projects such as the Cancer Genome Atlas. Scientists have amassed a wealth of information about which genes are mutated in which cancers, but they don’t always know which mutations are the most important.

If reading tumors’ mutations is the "first dimension" of the cancer genome, Fu says, what he and his colleagues want to construct is the "third dimension."

Related Resources:

• "Cancer Genomics Center, funded by the NCI, targets protein networks for drug discovery"

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