A combination of computational and experimental research led by the University of Pittsburgh has discovered specific cancer drug candidates that show promise for treating the respiratory condition pulmonary hypertension.
The researchers used an algorithm to find what are known as differential dependency networks (DDNs) of genes linked to cancer drug responses that can also overlap with other diseases such as pulmonary hypertension.
They discovered two drug candidates previously investigated to treat cancer that showed promise for treating the symptoms of pulmonary hypertension in human cells and in an animal model.
Pulmonary hypertension is a rare condition with around 1000 new cases per year in the U.S., affecting women more than men. People with this condition have high blood pressure in the arteries in the lungs, thought to be triggered by a combination of genetic and environmental factors that cause damage to the endothelial cells lining the blood vessels in the lungs. A few treatments to manage the symptoms are available, most of which dilate or relax the blood vessels, but these are relatively limited and there is no cure.
“Repurposing drugs can cut down the time and cost of developing treatments for rare diseases, which historically don’t receive much investment into research and drug development,” said senior investigator Stephen Chan, professor of medicine and director of the Vascular Medicine Institute at the University of Pittsburgh, in a press statement.
“Pulmonary hypertension is an example of a rare disease where there is an unmet need for new treatments, given its devastating consequences. We developed this pipeline to rapidly predict which drugs are effective… and get these treatments to patients faster.”
As described in the journal Science Advances, the researchers used an algorithm to search for cancer drugs and their targets that might impact genes known to be involved in the symptoms of pulmonary hypertension.
They found bromodomain and extra-terminal motif (BET) protein inhibitors, which have been investigated for their anticancer properties, have a mode of action reliant on a number of gene clusters one of which includes the gene LGALS8. The LGALS8 protein helps control endothelial cell death, something that is important for patients with pulmonary hypertension, making these good candidate drugs for treating this condition.
In addition, a candidate drug similar to piperlongumine, which is extracted from long pepper plants and has anti-cancer properties, was also shown to have potential for treating pulmonary hypertension when given to rats and mice with the condition. The actions of this compound depend upon the iron-sulfur biogenesis gene ISCU and were shown to limit endothelial cell death and, in so doing, improve symptoms of pulmonary hypertension.
“We identified crucial drug-gene axes central to endothelial dysfunction and therapeutic priorities for pulmonary hypertension,” write the authors.
“These results establish a wide-ranging, network dependency platform to redefine cancer drugs for use in noncancerous conditions.”
The authors now plan to test the compounds they identified further and hopefully bring them to clinical trials for patients with pulmonary hypertension. They also plan to look for more possible candidates for drug repurposing, both for this condition and others that are in need of new therapeutics.
“With this algorithm in hand, we may be able to repurpose existing cancer drugs for the treatment of other rare and emerging diseases,” said Chan.
