The cancer hypothesis of pulmonary arterial hypertension: the next ten years

In “The hallmarks of severe pulmonary arterial hypertension: the cancer hypothesis—ten years later” (2), the authors discuss paradigms that have come to govern our understanding of the pathobiology of pulmonary arterial hypertension (PAH) and how these have grown in parallel with those more traditionally associated with cancer biology. The present article points out a number of important shifts in the conceptualization of PAH as a cancer-like process that shares many of the molecular hallmarks of cancer described by Hanahan and Weinberg in their classic reviews on the topic (3, 4). Early observations of increased cell proliferation, apoptosis resistance, and inappropriate angiogenesis within PAH vascular lesions achieve special relevance in light of reports demonstrating evidence of genetic instability, impaired DNA repair mechanisms, metabolic switch, and epigenetic dysregulation in vascular cells isolated from PAH lungs (4, 7). Independent of which of these mechanisms is dominant at any time within the PAH lesion, it is reasonable to propose that the “PAH as a cancer-like process” paradigm can help us identify effective strategies currently used in oncology to identify novel biomarkers and therapies tailored to address each of these mechanisms. In the same way that precision medicine has improved cancer treatment, we have now started to make progress in implementing the use of deep phenotyping strategies as a potential approach to predict responses to therapy and clinical outcomes (10). It is also tempting to speculate that minimally invasive diagnostic approaches used in oncology such as the “liquid biopsy” could overcome the persistent lack of readily available lung tissue for preclinical studies and could even be used routinely to help diagnose and monitor PAH patients.

While pointing out the similarities between cancer and PAH, it is also important to recognize that we have significant limitations regarding the tools being used to carry out our mechanistic and preclinical studies. Dependence on cell culture models and animal models that do not capture the complexity of the lung pathology seen in PAH lungs limits our capacity to understand the interplay between the different cancer-like mechanisms reviewed by the authors. For instance, cells isolated from explanted lungs do not come exclusively from affected areas and represent a heterogeneous population that continues to change from passage to passage. Culture conditions can also induce phenotypic and genetic changes that could impact the metabolic activity and functional response of cells to experimental conditions (1). Researchers should take this into consideration when using Omics approaches for deep phenotyping of cell cultures since interpretation of these large data sets can be easily confounded by the potential variability introduced by the artificial culture systems. Regarding animal models, the review does an excellent job pointing out the shortcomings of the Sugen/hypoxia rat model, one of the best experimental models of PAH, and to what extent it allows us to study cancer-like properties seen in human samples. Currently, there is an active interest in developing humanized rodents and “lung on a chip” platforms as a way to overcome these limitations, but it remains to be seen to what extent they will be successful in addressing this challenge.

Despite these limitations, the scientific community has made a commitment to explore whether therapeutic approaches developed around these cancer-based mechanisms could have a place in the treatment of PAH. In the past five years, we have seen a Phase 1 study using dichloroacetate (DCA) to target the glycolytic switch (i.e., Warburg effect) associated with the gain in proliferation and apoptosis resistance seen in multiple PAH cell types (8). In this small study, the authors were able to show that DCA treatment was safe but the hemodynamic response was variable across the patient cohort. Through elegant studies, the authors were able to show that the presence of specific single-nucleotide variants in SIRT3 and UCP2 (genes involved in mitochondrial metabolism) could result in resistance to DCA through pyruvate dehydrogenase kinase (PDK)-independent inhibition of pyruvate dehydrogenase (PDH). This study highlights the complexity of the mechanisms involved in metabolic dysregulation in PAH but also provides a powerful lesson in how to use the readout of clinical studies to better understand the genetic foundation of individual responses to therapies.

The discoveries of the last 10 years continue to have significant repercussions in the way we approach drug discovery for PAH in 2020 and beyond. The old paradigm that described PAH as a disease of increased vascular tone can no longer be used as the only roadmap for drug discovery. To that, we now must add a new layer of cancer-related mechanisms that interact with the three classic PAH drug pathways (i.e., NO, endothelin, and prostaglandin signaling) to exert an undeniable influence in the initiation and progression of vasculopathy. While looking at the intersection of the new and old paradigms of PAH can be cause for trepidation, we should see the remarkable opportunities that are now open to attack the disease at a deeper level (6). The field has already embraced this attitude as evidenced by currently ongoing trials testing agents with known therapeutic value for cancer such as apabetalone (Phase 1, NCT03655704), Olaparib (Phase 1, NCT03251872), and the promising results of paclitaxel, trimetazidine, and verteporfin in preclinical studies (9). Lastly, the ongoing National Institutes of Health/ Pulmonary Hypertension Association sponsored Pulmonary Vascular Disease Phenomics (PVDOMICS) study promises to shed light on how these cancer-like processes fit into the overall evolution that each individual with PAH experiences during the natural history of the disease (5).

In conclusion, we should be proud of what we have accomplished in the last 10 years and should be excited for what’s yet to come. Let’s raise a glass and toast to the next ten years of discovery!

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

D.C., S.A., A.C., and V.A.d.J.P. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.