Penn Medicine research suggests more cancers can be treated with drugs than previously believed

March 14, 2023
The study used the world’s largest supercomputer to search for hidden, targetable regions.

Up to 50 percent of cancer-signaling proteins once believed to be immune to drug treatments due to a lack of targetable protein regions may actually be treatable, according to a new study from the Perelman School of Medicine at the University of Pennsylvania. The findings, published this month in Nature Communications, suggest there may be new opportunities to treat cancer with new or existing drugs.

Researchers, clinicians, and pharmacologists looking to identify new ways to treat medical conditions—from cancer to autoimmune diseases—often focus on protein pockets, areas within protein structures to which certain proteins or molecules can bind. While some pockets are easily identifiable within a protein structure, others are not. Those hidden pockets, referred to as cryptic pockets, can provide new opportunities for drugs to bind to. The more pockets scientists and clinicians have to target with drugs, the more opportunities they have to control disease.

The research team identified new pockets using a Penn-designed neural network, called PocketMiner, which is artificial intelligence that predicts where cryptic pockets are likely to form from a single protein structure and learns from itself. Using PocketMiner—which was trained on simulations run on the world’s largest super computer—researchers simulated single protein structures and successfully predicted the locations of cryptic pockets in 35 cancer-related protein structures in thousands of areas of the body. These once-hidden targets, now identified, open up new approaches for potentially treating existing cancer.

What’s more, while successfully predicting the cryptic pockets, the method scientists used in this study was much faster than previous simulation or machine-learning methods. The network allows researchers to nearly instantaneously decide if a protein is likely to have cryptic pockets before investing in more expensive simulations or experiments to pursue a predicted pocket further.

At the end of the team’s experiments, the neural network identified probable cryptic pockets in 50 percent of protein structures tested that were previously thought to be “undruggable” and to contain no pockets. That can mean many cancers once thought untreatable with drugs could be treated effectively.

In their paper, the researchers highlighted two key protein structures, within cancer-signaling pathways, where cryptic pockets likely exist, which they say should be pursued when designing new drugs. The first, WNT2 protein in the Jak/Stat pathway is an integral part of cancer signaling in many solid tumors. The second is PIM2, a particular enzyme that is implicated as a driver of several types of cancer, including those of the lung, prostate, and breast as well as leukemia, and myeloma.

Penn Medicine release