Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 6

Novel Therapeutic Agents for Pulmonary Arterial Hypertension: Role of Signaling Inhibitors

Robyn J. Barst, M.D.
Columbia University

Until in the early nineties, pulmonary arterial hypertension (PAH) was a uniformly fatal, with a median life expectancy of only a few years. Since then, a total of 18 multicenter, randomized, controlled, trials of prostacyclin derivatives, endothelin receptor antagonists and a phosphodiesterase-5 inhibitor have been reported in a total of 2248 patients, with favorable results. This is a remarkable achievement given the rarity and severity of the disease. All these trials with the exception of one, interrupted because of side effects, have reported a significant but moderate increase in exercise capacity, together with improvements in functional class, clinical stability, hemodynamics and quality of life, though less constantly and often to a minor degree. However, none of the treatments tested so far has offered a cure.

More recently, our increased understanding of additional pathways in PAH offers the opportunity to develop novel therapeutic strategies. It is now well appreciated that the pathobiology of PAH includes endothelial cell dysfunction, and proliferation and migration of vascular smooth muscle cells (VSMc). The process of pulmonary vascular remodeling involves all layers of the vessel wall and is complicated by the heterogeneity within each component of the pulmonary arterial wall. Indeed, each cell type (endothelial, smooth muscle and fibroblast) as well as inflammatory cells and platelets, are postulated to play a significant role in PAH. Growth factors have been implicated in the abnormal proliferation and migration of VSMc, e.g. PDGF, EGF, VEGR, elastase, MMPs, with upregulation and activation of various signaling pathways becoming a self-perpetuating vicious cycle, which regardless of the initiating trigger or stimulus, results in progressive pulmonary vascular obstructive disease. However, one must remain cognizant that with any attempt to interrupt one vicious cycle, other pathways that may also be involved could either further reverse or further accelerate the pulmonary vascular changes. In addition, with mutations in BMPR 2, activin receptor-like kinase, endoglin and TGF-beta receptors reported in patients with PAH, we must simultaneously explore the potential roles of angiogenesis, apoptosis and proteolysis in the pathobiology of PAH. And regardless of the mechanism(s) of vascular occlusion, regeneration of lung microvasculature may also be a novel and effective therapeutic strategy for restoring the pulmonarv vascular bed in PAH. This raises the question of whether endothelial progenitor cells, which normally repair and regenerate blood vessels, could increase microvasculaar perfusion in damaged pulmonary vascular beds in PAH.

As cancer and PAH share pathophysiology of aberrant endothelial cell and SMC proliferation, signaling inhibitors could prove efficacious in the treatment of PAH by restoring apoptosis and anti-proliferation in the pulmonary vascular bed. Several examples of the ongoing studies aimed at altering signaling pathways will be discussed in this session.

However, many questions remain – will it be possible to restore normal signaling in genetically and/or environmentally predisposed individuals before the process of vascular disease begins? Unfortunately, research in PAH remains significantly limited by: no highly faithful animal model of disease to reassure efficacy for human trial; phase II trials in limited number of patients are prone to alpha and beta errors; preventive and remodelling therapies may take years to show effect; limited pool of patientsfor new trials; and new therapies must piggback on proven drugs, enlarging treatment cells. However, despite these impediments, the future of PAH research for novel therapeutic drugs is quite bright by exploring gene therapy and studying potential signaling inhibitors as we concomitantly develop second and third generation prostacyclin analogues, ERAs and PDE inhibitors.

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