PITTSBURGH, PA – By combining computational and experimental approaches, researchers at the University of Pittsburgh School of Medicine (Pitt) and Prairie View A&M University have identified promising cancer drugs for the treatment of pulmonary hypertension, or PH, a rare and incurable lung disease.
Posted in Scientists progress, study used a new algorithm to identify candidate cancer drugs for PH. Two of these compounds improved markers of the disease in human cells and rodents. The results support wider use of this drug reassignment platform for other non-cancerous conditions that do not yet have effective treatments.
âDrug reuse can reduce the time and cost of developing treatments for rare diseases, which historically do not receive a lot of investment in drug research and development,â said lead author Stephen Chan, MD. , PhD, Professor of Medicine and Director of the Pitt Vascular Institute of Medicine and University of Pittsburgh Medical Center (UPMC). âPulmonary hypertension is an example of a rare disease for which there is an unmet need for new treatments, given its devastating consequences. We have developed this pipeline to quickly predict which drugs are effective for PH and deliver those treatments to patients faster. “
Pulmonary hypertension is a type of high blood pressure that occurs in the vessels that carry blood from the heart to the lungs. As the disease progresses and the heart has to work harder against these high pressures, it can lead to heart failure, multiple organ dysfunction, and death. PH affects people of all ages, but more often strikes young women than men.
One of those young women is Allison Dsouza, a 24-year-old nurse who not only lives with the disease herself, but also treats patients with PH as part of UPMC’s lung transplant program. She was diagnosed with PH in her last year of high school after having difficulty walking to her car and engaging in hobbies like horseback riding. According to Dsouza, she was the sickest patient with the highest lung pressures her doctors had seen.
PH is believed to be triggered by environmental and genetic factors that damage the endothelial cells that line blood vessels, leading to inflammation and abnormal repair that restrict blood flow or cause the tree’s thinnest branches to be lost. pulmonary vessels.
Medicines currently available for PH dilate or relax these blood vessels, which may relieve symptoms and prolong the time it takes for the disease to progress, but they are not curative. Dsouza is given a medicine called Remodulin which is delivered continuously by a pump inserted under his skin. A few months after starting treatment, she ran a 5-kilometer race, started playing polo on horseback, and enrolled in college to study nursing.
âThe treatments are phenomenal, but they are also a huge burden on life,â said Dsouza. âSubcutaneous treatments cause severe pain and intravenous treatments pose a huge risk of infection from which people can actually die. The drug saves lives, but the side effects can kill you. And for some people, the therapies don’t work.
According to Chan, there is a need for drugs that target the origins of pulmonary hypertension.
Given the evidence that PH and cancer share many characteristics, Chan hypothesized that large molecular data from cancer studies could be used to predict which anti-cancer drugs might target PH as well. To make these predictions, Chan collaborated with lead author Seungchan Kim, PhD, Chief Scientist and Executive Professor of Electrical and Computer Engineering at Prairie View A&M University. They built a computer platform that analyzed gene expression data from 800 cancer cell lines exposed to hundreds of cancer treatments and assessed the rewiring of gene networks associated with drug responses in these cells.
âWhen we overlay these arrays with arrays of PH-specific genes, we can predict which drugs may be effective in treating PH,â Kim explained.
The platform categorized each drug based on how its action depended on rewiring the PH-specific gene arrays, and the researchers chose to further study two highly classified compounds: I-BET762 and BRD2889.
In human lung endothelial cells, I-BET762 and BRD2889 modulated platform-predicted PH gene arrays, genes that lead to cell death under low oxygen and inflammatory conditions, processes that promote PH .
A drug in the same class as I-BET762 is currently being tested for PH in clinical trials conducted by co-authors at Laval University. Computer analysis and experiments have identified new molecular pathways for this class of drugs, indicating that the platform may offer new information about drugs already under investigation. Another promising compound, BRD2889, which is an analogue of piperlongumine, a compound derived from long pepper plants with anti-cancer properties, had not previously been studied for the treatment of PH.
When Chan and lead author Imad Al Ghouleh, PhD, assistant professor of medicine at Pitt, gave BRD2889 to mice and rats with PH, the symptoms of the disease were reversed, suggesting that this compound had a potential as a new drug against PH. The researchers have filed a provisional patent application for BRD2889, and they plan to move the compound into clinical trials in the future.
With evidence that the drug candidates identified by the algorithm are effective in treating PH in animals, the researchers plan to go back and take a closer look at other compounds predicted as potential treatments for the disease. And according to Chan, the applications of this study go far beyond PH.
“With this algorithm in hand, we may be able to reuse existing cancer drugs for the treatment of other rare and emerging diseases,” Chan said.
The other researchers in the study were: Vinny Negi, PhD, Jimin Yang, PhD, Andres Pulgarin, PhD, Adam Handen, Jingsi Zhao, Yi Yin Tai, Ying Tang, Miranda K. Culley, PhD, Qiujun Yu, MD, PhD , Patricia Forsythe, Anastasia Gorelova, PhD, Annie M. Watson, Yassmin Al Aaraj, Taijyu Satoh, MD, PhD, Maryam Sharifi-Sanjani, PhD, Arun Rajaratnam, MD, and John Sembrat, all from Pitt or UPMC; Gil Speyer, PhD, Arizona State University; Steeve Provencher, MD, and SÃ©bastien Bonnet, PhD, both from Laval University; Xianglin Yin, PhD, and Mingji Dai, PhD, both from Purdue University; Sara O. Vargas, MD, Children’s Hospital of Boston; Mauricio Rojas, MD, Ohio State University; StÃ©phanie Torrino, PhD, and Thomas Bertero, PhD, both from the UniversitÃ© CÃ´te d’Azur; and Bridget K. Wagner, PhD, and Stuart L. Schreiber, PhD, both from Harvard University and the Broad Institute at MIT and Harvard.
– This press release was originally published on the University of Pittsburgh Medical Center website