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Year : 2013  |  Volume : 8  |  Issue : 2  |  Page : 69-70
Pulmonary hypertension: Another light in the dark tunnel. Learning the lesson from cancer

Saudi Association for Pulmonary Hypertension, Pulmonary Division, Riyadh Military Hospital, Riyadh 11159, Saudi Arabia

Date of Submission14-Jun-2012
Date of Acceptance19-Feb-2013
Date of Web Publication30-Mar-2013

Correspondence Address:
Majdy Idrees
Saudi Association for Pulmonary Hypertension, Pulmonary Division, Riyadh Military Hospital, PO Box 7897 (C110), Riyadh 11159
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1817-1737.109813

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How to cite this article:
Idrees M. Pulmonary hypertension: Another light in the dark tunnel. Learning the lesson from cancer. Ann Thorac Med 2013;8:69-70

How to cite this URL:
Idrees M. Pulmonary hypertension: Another light in the dark tunnel. Learning the lesson from cancer. Ann Thorac Med [serial online] 2013 [cited 2023 Feb 2];8:69-70. Available from:

Pulmonary hypertension (PH) is a fatal disease. If untreated, the median survival is 2.8 years. [1] The disease is clinically characterized by a progressive increase in pulmonary vascular resistance (PVR) secondary to continuous obliteration of pulmonary arteries by a proliferative process involving all pulmonary vascular layers. [2]

In the last PH world congress at Dana Point, the disease was classified into five groups. [3] Group 1, which is called pulmonary arterial hypertension (PAH), has gained a lot of interest during the last few years. Such interest has lead to a better understanding of the complex disease pathobiology and, subsequently, the development of many effective drugs that improve hemodynamics, exercise performance, quality of life, and survival. [4]

Different pathobiological mechanisms triggered by endothelial cells dysfunction have been clearly identified and observed in PAH. Such mechanisms include smooth muscle vasoconstriction, shear stress abnormality, pulmonary vascular wall remodeling, inflammation, and in-situ thrombosis. [5] Plexogenic arteriopathy, however, is the most characteristic feature of PAH, in which the pre-capillary vessels display varying degree of abnormalities involving proliferation of both the intima and media. [6]

During the last decade, significant advances have been achieved in the management of PAH. The availability of new classes of vasodilators that also modify cell proliferation and target-specific active pathobiological pathways, so-called targeted therapy, has been considered as a major breakthrough in treating this condition. The first class of medication is the prostanoid, which is a very potent vasodilator of all vascular beds and potently inhibit proliferation of pulmonary smooth muscle via a cAMP-dependent pathway. [7] The second class of targeted medication is the endothelin-1 receptor antagonists that inhibit the potent vasoconstriction and smooth-muscle mitogenic effects of endothelin-1 on pulmonary vasculature by inhibiting its effect on endothelin A and B receptors located on pulmonary smooth muscles. [8] The third class of medication is the phosphodiesterase-5 inhibitors that modulate the content of cGMP in vascular smooth muscle by preventing its degradation by phosphodiesterase-5 enzymes. This mechanism leads to augmentation of pulmonary vasodilatation and inhibit smooth muscle proliferative activities. [9] Despite their antiremodeling/antiproliferative effect, these drugs are largely considered as vasodilators and certainly more specific treatment targeting other active signaling are needed before long-term control of the disease is to be achieved.

Recent studies have shifted our understanding toward the neoplastic features of PAH by focusing on the uncontrolled proliferation of many cellular layers and the bypassing of the mitochondria-controlled apoptosis process. [2] Such imbalance between cell generation and cell termination/deaths raised the concept of "pulmonary circulation neoplasm" theory. Furthermore, the continuous cell mitogenic activities in PAH even under hypoxic conditions by utilizing anaerobic glycolysis for energy (i.e., ATP) production and the inhibition of the mitochondrial capacity to maintain the balance of cell birth: death ratio are very similar to many cancer situations. [2]

Consequent to this recent understanding, a phase III study using anti-proliferative, anti-cancer, Tyrosine Kinase inhibitor (TKIs), therapy (imatinib) in advanced PH patients showed a very impressive positive effect on the patient exercise capacity (6 minute walk test) and on the disease hemodynamics by significantly reducing the PVR and improving cardiac output. [10]

Despite this encouraging early result of TKIs and the use of anticancer therapy in PH management, an important question remains: "did we really learn the lesson from cancer?"

The following are important considerations to be learned from cancer before TKIs (or other anti-cancer therapy) can be used in treating "pulmonary circulation neoplasm".

  • Recent evidence in non-small cell lung cancer (NSCLC) has provided very important insights into the molecular basis of this disease and has also revealed an important concept for targeting tyrosine kinases by rationally selected therapies toward a spectrum of genetic mutations/lesions found in NSCLC. [11] The significant variation in mutational profiles seen in NSCLC patients suggests that each tumor represents a distinct disease state that can only be effectively treated with a precise therapy that targets the specific combination of genetic changes unique to each tumor. This finding has created the concept of " personalized treatment" to each case and led to a breakthrough in management of NSCLC. [12]
  • The complexity of genetic heterogeneity and pathway redundancy that characterize advanced NSCLC provide an insight about the limitations of single-agent therapies and suggests that more sophisticated chemotherapeutic regimen that target multiple pathways at the same time will be required to effectively treat this disease.
Based on these tremendous advances in understanding the genome sequencing and mutation in NSCLC and its therapeutic implications, we strongly believe that PAH treatment should probably follow the same path.

One theme is to determine the genetic alterations to key growth factor signaling pathways that regulate cell proliferation, survival, and migration before starting therapy. It is only in those patients with very specific gene mutation and active signal propagation by kinase cascades, suggesting that they would be excellent targets for rationally designed TKIs, should treatment with these agents considered.

The second theme is toward upfront combination therapy by more than one chemotherapeutic agent. This will probably help not only to overcome drug resistance mechanism, but also to address different active signaling pathways that are likely to be present in most, if not all, PAH patients.

We believe that the time has arrived toward adopting "antineoplastic therapy" in the treatment of PAH, and not simply counting on vasodilator therapy. The recent small effort toward using this approach has shown some benefit, but, in our opinion, was not optimally utilized.

Learning our lesson fully from cancer medicine should hopefully lead us to the light at the end of the dark tunnel.

   References Top

1.D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343-9.  Back to cited text no. 1
2.Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:S13-24.  Back to cited text no. 2
3.Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-54.  Back to cited text no. 3
4.Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009;30:394-403.  Back to cited text no. 4
5.Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109:159-65.  Back to cited text no. 5
6.Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004;43:S25-32.  Back to cited text no. 6
7.Clapp LH, Finney P, Turcato S, Tran S, Rubin LJ, Tinker A. Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery. Am J Respir Cell Mol Biol 2002;26:194-201.  Back to cited text no. 7
8.Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res 2004;61:227-37.  Back to cited text no. 8
9.Tantini B, Manes A, Fiumana E, Pignatti C, Guarnieri C, Zannoli R, et al. Antiproliferative effect of Sidenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol 2005;100:131-8.  Back to cited text no. 9
10.Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galié N, et al. Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension: Results of the Randomized IMPRES Study. Circulation 2013;127:1128-38.  Back to cited text no. 10
11.Vlahovic G, Crawford J. Activation of tyrosine kinases in cancer. Oncologist 2003;8:531 - 8.  Back to cited text no. 11
12.Gazdar AF. Personalized medicine and inhibition of EGFR signaling in lung cancer. N Engl J Med 2009;361:1018 - 20.  Back to cited text no. 12


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