Crystal structure of Myc and Max in complex with DNA. Credit: Mark Absturz.
The cancer gene MYC is perhaps the most important one. In many cancers, it is overexpressed, leading cells to grow and divide too rapidly. Research shows the activation of MYC may affect 70% or more of all human cancers. On top of that, it can direct other genes to be built or silenced, it affects cell growth and cell apoptosis. MYC also affects the repair process of damaged DNA, and the growth of blood vessels.
So why not just design medications to inhibit MYC? If only it was that simple. MYC has a very complex structure that has repeatedly prevented drugs from having any affect on it.
Now, after 15 years, researchers in Florida and Germany have discovered that the key to regulating MYC—and other critical cancer genes—is to target the genes’ RNA with medicines.
‘Undruggable’ targets
Before Matthew Disney, of The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology and the UF Health Cancer Center, began his research, RNA represented a difficult drug-targeting challenge.
Comprising just four nucleotides, RNA wears many hats—it reads genes, assembles proteins and is recycled to carry out other work in the cell. Its diverse and changeable structures led many to believe RNA-directed medicines were a pipe dream.
But over the course of 15 years, Disney and his team have identified many conserved, druggable RNA structures. In their latest research, published in Nature, the team discovered around 2,000 new RNA structures that are able to bind drug-like small molecules, and identified six new chemotypes able to bind RNA.
“We basically have created an encyclopedia of druggable RNA folds,” said Disney.
The scientists’ latest approach directs cells’ recycling enzymes to cancer genes’ RNA and cuts up key segments to prevent them from doing harm.
“We found it wasn’t enough to bind these targets’ RNA,” explained Yuquan Tong, a graduate student in Disney’s lab. “That alone didn’t make enough of an impact. We had to also modify the compounds so that they could recruit targeted small-molecule RNA degradation enzymes.”
To edit out these disease-causing RNA segments, Disney developed a method to attach a chemical fishing hook to the molecules—one designed to catch the cell’s RNA recycling enzymes. It worked as planned. In the lab, the RNA recycling enzyme chopped up the RNA that the drug molecule was attached to, preventing the disease-causing proteins from being built.
The team called their hybrid molecule a RiboTAC, short for “ribonuclease-targeting chimera.”
“With the degrader added, we started seeing these ‘undruggable’ cancer RNAs reduced by 35%, 40%, 50% or more. This caused cancer cells to die and cleared tumors in mouse-based studies of breast cancer that spread to lungs,” said Disney.
When scientists at nearby Moffitt Cancer Center tested the efficacy of the RiboTAC compounds, they were excited to see that they effectively kill B-cell lymphomas driven by MYC, which are known to be aggressive and difficult-to-treat tumors.
Not only did the tactic work against the MYC cancer gene, but two other challenging cancer genes as well—JUN and MIR155. Activation of JUN has been seen in more than 20 different cancer types, including glioblastoma, breast, prostate, lung, colorectal cancer and more. Meanwhile, MIR155 is known to drive inflammation and the growth and spread of many cancers, including breast, kidney, gastric and other cancers.
The researchers say their study shows that compound classes inspired by natural products provide a rich, new source for targeting RNA disease targets in general. The compounds are providing a path to make more and better drugs, and providing a banquet of new RNA structures to test in other disease settings.
“This is a starting point,” Disney said. “It’s showing us where to go to build small-molecule, RNA-targeting medicines that could eventually treat patients with diseases like aggressive cancers that currently have poor or no options. This new data also shows us that this approach could have many other disease applications.”