Nav: Home

New understanding of pulmonary hypertension leads to promising drug targets

August 22, 2016

A groundbreaking new study led by researchers from the University of Pittsburgh and UPMC has identified a new group of compounds that could have robust effects in treating pulmonary hypertension (PH), an enigmatic but sometimes fatal disease of the blood vessels of the lungs that currently has no cure. The findings, which were published today in the Journal of Clinical Investigation, highlight the use of these drugs to alter vessel stiffness and its downstream control of metabolism, a link previously unknown for people suffering from the progressive disease.

"If we aim to cure this disease, the next set of medications and treatments should be those that target the origin at the molecular level," said Stephen Y. Chan, M.D., Ph.D., director of the UPMC Center for Pulmonary Vascular Biology and Medicine at the Vascular Medicine Institute at Pitt, and senior author of the study. "As a community, we are struggling right now to understand those origins of PH, and this study aimed to address that untapped need."

Affecting tens of millions of people worldwide, PH is high blood pressure in the arteries in the lungs, which makes it difficult for blood to flow from the heart to the lungs. Symptoms of the disease, which can lead to heart failure, include shortness of breath, fatigue and chest pain; and, in its early stages, might not be noticeable for months or even years. Often a life-threatening condition, it becomes progressively worse, making early and accurate diagnosis important to allow treatments that extend and improve the quality of life for many patients.

To make these discoveries, Dr. Chan and his colleagues used a comprehensive array of tools derived from cells and tissues of animal and humans with PH. Notably, these findings also were relevant to PH caused by human immunodeficiency virus (HIV) infection--a particularly mysterious form of this disease where the underlying molecular processes have remained unknown for decades.

Dr. Chan's team found that stiffening or hardening of the vessels in the lung is an early event in PH that triggers the activation of two critical signaling molecules called YAP and TAZ. These molecules in turn activate a protein called GLS1, which controls how cells in the vessel produce and use energy.

"The link between vessel hardening and energy production is absolutely central to this disease," said Dr. Chan. "That discovery offers us so many new ways to design drugs tailor-made to stop PH in its tracks."

As proof-of-concept, Dr. Chan's team tested both the YAP inhibitor verteporfin, a Food and Drug Administration-approved medication for macular degeneration, and a GLS1 inhibitor called CB-839, which is in clinical trials for cancer. They found that both of these compounds displayed robust effects in improving PH in a rodent model of disease.

"We are very encouraged by these results," said Dr. Chan. "We are working to repurpose these drugs for treatment of human PH, which now can include long-neglected disease types such as HIV-related conditions and others. We hope that we can do so without the delay of decades that often happens when developing new compounds from scratch."

Given that vessel stiffness is prevalent in other diseases--including cancer progression--these results also may be important beyond PH, noted Dr. Chan.

"There is always more work to be done," he said. "But, we feel this represents a significant milestone in our quest to cure this disease."
-end-
About the University of Pittsburgh: A nonsectarian, coeducational, state-related, public research university founded in 1787, the University of Pittsburgh (Pitt) is a member of the prestigious by-invitation-only Association of American Universities and internationally renowned as a leading center of learning and research in the arts, sciences, humanities, professions, and health sciences. Comprising a Pittsburgh campus, which is home to 16 undergraduate, graduate, and professional schools, and four Western Pennsylvania regional campuses, Pitt offers nearly 400 distinct degree programs and confers more than 7,500 degrees annually. Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998, and is ranked among the top 10 American research universities nationally in terms of total federal science and engineering research and development obligations. For more information, visit http://www.pitt.edu.

About UPMC

A world-renowned health care provider and insurer, Pittsburgh-based UPMC is inventing new models of patient-centered, cost-effective, accountable care. It provides more than $892 million a year in benefits to its communities, including more care to the region's most vulnerable citizens than any other health care institution. The largest nongovernmental employer in Pennsylvania, UPMC integrates 60,000 employees, more than 20 hospitals, more than 500 doctors' offices and outpatient sites, and a more than 2.9 million-member Insurance Services Division, the largest medical and behavioral health services insurer in western Pennsylvania. Affiliated with the University of Pittsburgh Schools of the Health Sciences, UPMC ranks No. 12 in the prestigious U.S. News & World Report annual Honor Roll of America's Best Hospitals. UPMC Enterprises functions as the innovation and commercialization arm of UPMC while UPMC International provides hands-on health care and management services with partners in 12 countries on four continents. For more information, go to UPMC.com.

http://www.upmc.com/media

University of Pittsburgh Schools of the Health Sciences

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...