A protein activated while cancer is developing in the body may have a close connection to pulmonary arterial hypertension (PAH), reports a research team from Canada who tested a unique form of therapy targeting this protein.¹

Sharing Distinct Pathologies

The protein is known as survivin, which blocks a process of pre-programmed cell death known as apoptosis (ap-ahp-TOE-sis) in the body. Apoptosis is a natural event, allowing the body to kill off old or surplus cells.

Researchers at the University of Alberta found that survivin, in addition to its role in cancer progression, is also heavily active in the lung arteries of both people and animals. "The most intriguing aspect is we've shown for the first time that this cancer protein is also expressed [activated] within the blood vessels of the lung in patients suffering with PAH, but not in normal human blood vessels, making survivin a very attractive target for selective intervention," explained Evangelos Michelakis, MD, director of the Pulmonary Hypertension Program at the University of Alberta, and the study's lead investigator.

Armed with this new information, the study team developed an inhaled form of gene therapy that targets survivin in people with PAH. It works by delivering a mutant, or inactive, form of the protein by way of a virus that travels through the bloodstream to the naturally produced, active survivin in the body. (The virus has its genes altered so that it does not cause disease as a normal virus would. Instead, viruses used in gene therapy serve only as transporters for the therapy to the targeted site in the body).

Once the mutant survivin reaches the naturally-produced survivin, it inhibits the protein. Thus, apoptosis can continue.

The treatment reversed PAH progression in a group of rats and both improved their heart function and survival odds. While results found in animals aren't always reproducible in humans, the research team is hopeful that will happen eventually.

The Role of Survivin

Michelakis and his colleagues believe that survivin may drive excessive cell growth by inhibiting apoptosis in the lung's blood vessels in people with PAH, though this hasn't been confirmed yet. This is exactly how the protein works in cancer patients.^2,3

Similarly in PH, cells in the lungs' blood vessels grow excessively, thickening the blood vessels and making it more difficult for blood to pass through, and raising the blood pressure in these arteries. "This makes the proliferation of lung blood vessels in this disease 'a form of cancer'," Michelakis explained. "We've demonstrated for the first time that, like cancer, apoptosis is suppressed in the lung blood vessel wall in this disease."

Thus far, one of the biggest challenges in treating pulmonary hypertension has been the difficulty in determining what makes the tissue found in the lining of the lungs' blood vessels grow out of control, he added. Further, any therapies that are developed must target the excessive cell growth in these blood vessels while leaving normal cells in the rest of the body alone.

Study Feedback

In an editorial accompanying the study,⁴ Serge Adnot, MD, PhD, with the Institut National de la Santé et de la Recherche Médicale (INSERM) in France wrote that significant questions were raised by the study. "These findings raise important issues regarding the role of survivin in the [origin] of PAH, its value as a prognostic indicator, and its use as a target for new therapeutic strategies."

"There is considerable dissimilarity among patients with PAH regarding disease progression rates and treatment responses," Adnot wrote. "Whether the level of survivin expression in pulmonary vessels reflects the potential for disease progression remains to be tested."

1. McMurtry MS, Archer SL, Altieri DC et al. Gene therapy targeting surviving selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 2005 Jun 1;115(6):1479-91.
2. Lu X, Lee M, Tran T, Block T. High level expression of apoptosis inhibitor in hematoma cell line expressing hepatitis B virus. Int J Med Sci 2005;2(1):30-5.
3. Zaffaroni N, Pennati M, Daidone MG. Survivin as a target for new anticancer interventions. J Cel Mol Med 2005 Apr-Jun;9(2):360-72.
4. Adnot S. Lessons learned from cancer may help in the treatment of pulmonary hypertension. J Clin Invest 2005 Jun 1;115(6):1461-3.