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Inhibiting a Cancer Cell Proliferation Gene May Be a New Option for Treating Pulmonary Hypertension

The rapid cell division and excessive cell production observed in pulmonary hypertension and cancer may be due to the PBK gene.

Scientists at the Medical College of Georgia at Augusta University have discovered that a gene, known as PBK, which encodes for PDZ-Binding Kinase that is overexpressed in some aggressive cancers such as bladder, brain, liver, and lung tumours, may be a key factor to the excessive cell proliferation that leads to the thickening of pulmonary arteries and eventually causes the right ventricle of the heart to fail. According to Dr. David Fulton, director of the Vascular Biology Center at the university, the study has presented the first evidence of PBK being upregulated in both animal models and the lung tissue of patients with progressive and deadly pulmonary hypertension.

Pulmonary hypertension is a rare, progressive condition that is characterised by an unhealthy remodelling of the pulmonary arteries, specifically in the form of shrinking the lumen of blood vessels, which can result in increased resistance inside pulmonary arteries, enlargement, and ultimately the failure of the right ventricle of the heart. This invites the recruitment of fibroblasts, immune cells, and smooth muscle cells to these sites. While the cause of this ailment is unknown in 25 per cent of cases, scientists believe that genetics may be an important factor. Pulmonary hypertension may also stem from other conditions like congenital heart abnormalities, cirrhosis of the liver, drugs like methamphetamine and cocaine, infections like HIV and schistosomiasis, and scleroderma.

In their study, the researchers have found that the rapid cell division and resultant excessive cell production in pulmonary hypertension are similar to that observed in cancer. Upon closer examination, Dr. Scott Barman, pulmonary vascular biologist in the MCG Department of Pharmacology and Toxicology, reported that PBK is upregulated in the middle layer of the walls of pulmonary arteries where the smooth muscle cells reside and where they, together with elastic and connective tissue, help control the size of blood vessels.

Using rat and mouse models of pulmonary hypertension, Barman and the team found early evidence that PBK inhibitors can reduce the unhealthy remodelling of blood vessels and improve heart and lung function. They used a reversal model that mimics how drugs would be used in people and administered treatment when animal models began to display symptoms of the disease.

Having confirmed that changes in PBK expression can affect the proliferation of smooth muscle cells, Fulton and Barman are now embarking on another study under a $2.5 million grant from the National Heart, Lung and Blood Institute to better understand the PBK pathway and the impact of PBK inhibitors. At present, PBK inhibitors are already being investigated for certain types of aggressive cancers.

With the new grant, the scientists will be learning more about how exactly PBK regulates smooth muscle cell proliferation in the pulmonary arteries. By using a rat with PBK gene knocked out, the researchers tested two PBK inhibitors – OTS514 and TOPK-32 – that have shown promise to halt abnormal cancer cell proliferation at different doses. Barman explained that they are hoping to determine if higher doses would further reduce cell proliferation. To date, their studies have only shown that small doses have only yielded “amelioration.”

“We were looking for genes involved in promoting smooth muscle proliferation that [are also] in cancer,” said Fulton. “It’s the uncontrolled proliferation that is the problem, and we are looking for targets that we could exploit to decrease it.”

Currently, standard treatments such as vasodilators and oxygen therapy only help to address symptoms but do not halt the progression of the disease. The only potential cure remains to be a lung transplant. Treatment-wise, Fulton noted that PBK is not the only regulator of cell proliferation. Even when PBK is knocked out, animals can still develop. Upstream of PBK is YAP1, or yes associated protein 1, a transcription factor which activates genes that enable cell proliferation and mute those that are pro-apoptotic. YAP1 is also upregulated in pulmonary hypertension, where it boosts PBK activity in smooth muscle cells inside the walls of pulmonary arteries. Downstream, the scientists observed that PBK upregulates PRC1 or protein regulator of cytokinesis 1, which results in unhealthy remodelling of pulmonary arteries and pulmonary hypertension. In the specific case of pulmonary hypertension, PBK is an early player.

“We think YAP is an upstream driver of proliferation that activates PBK expression in the pulmonary smooth muscle cells,” said Fulton. Although expressed in various cell types, YAP’s unique ability to activate PBK makes PBK itself a good, druggable target, Fulton added.

Once the scientists complete their five-year term of the new grant, they expect to gain solid scientific evidence about PBK’s therapeutic potential, which will help drive PBK inhibition to become an adjunct therapy that can more directly target a clear point of action in the disease process. An effective inhibitor could also offer a simpler and more affordable therapeutic option. [APBN]

Source: Medical College of Georgia at Augusta University