favorably with erlotinib, the existing treatment option. However, the objective
responses to this therapy occurred in only 4% of patients, and the median survival
in the entire cohort was nevertheless just 6.4 months. Two other phase II trials using
the combination of azacitidine and entinostat in lung cancer are still ongoing
[121]. The results of these trials will hopefully clarify the potentially synergistic
effect between HDACi and DNMTi.
Finally, an interesting ongoing phase I clinical trial investigates the efficacy of
inhaled azacitidine in patients with advanced NSCLC [121]. Generally, azacitidine is
administered by subcutaneous injections, leading to systemic exposure. However,
localized delivery of the drug to the lungs by means of inhalation was proven highly
effective in animal models, because it was associated with longer survival, less
toxicity, and less lung cancer burden compared to subcutaneous injection
[122]. The results of that study sparked the initiation of the phase I trial. The outcome
of this trial will be interesting as it only investigates the effect of inhaled azacitidine,
not in combination with other therapies, which as a single-agent therapy has so far
been unsuccessful. A caveat for the use of inhaled therapies in lung cancer is that
between 30 and 40% of patients will have systemic metastases at the time of clinical
diagnosis [123]. Logically, a therapy localized to the lungs will then need to be
combined with a more systemic one.
5 Conclusions and Future Directions
Progress has been made in the chemotherapy of lung cancer by employing drugs that
influence the reversible posttranslational and post-replicative modifications of proteins and DNA, respectively. However, optimum treatment regimens with such
drugs still need to be defined, and it is clear that mostly a combination with another
drug is required. In that sense the triple therapy of a HDACi, a DNMTi, and an
immune checkpoint inhibitor is an interesting approach that is currently being
investigated. Additionally, other influencers of PTMs, like inhibitors of KDMs, are
in clinical trials for lung cancer [121]. It is to be expected that in the future an even
broader range of compounds that influence the state of PTMs will be studied in
combination therapies for lung cancer.
The results of the studies in lung cancer are highly relevant to other lung diseases
like asthma and COPD, because one way to view the airway remodeling observed in
asthma and COPD is to compare it to benign tumor growth. For instance, in both
cases cell proliferation is out of control, and tissue boundaries are weakened.
Therefore, as in lung cancer therapy, using drugs that regain control of tissue
proliferation and architecture might be promising in asthma and COPD. Yet, as
mentioned in this chapter, the study of HDACi and other influencers of PTMs in
these diseases is still in the proof-of-principle stage. The initial in vivo preclinical
studies are nonetheless promising, especially in the case of HDACi. In mouse
models of asthma and COPD, application of several HDAC inhibitors has shown
to result in a broad range of beneficial effects. Local administration of HDACi at
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
445
responses to this therapy occurred in only 4% of patients, and the median survival
in the entire cohort was nevertheless just 6.4 months. Two other phase II trials using
the combination of azacitidine and entinostat in lung cancer are still ongoing
[121]. The results of these trials will hopefully clarify the potentially synergistic
effect between HDACi and DNMTi.
Finally, an interesting ongoing phase I clinical trial investigates the efficacy of
inhaled azacitidine in patients with advanced NSCLC [121]. Generally, azacitidine is
administered by subcutaneous injections, leading to systemic exposure. However,
localized delivery of the drug to the lungs by means of inhalation was proven highly
effective in animal models, because it was associated with longer survival, less
toxicity, and less lung cancer burden compared to subcutaneous injection
[122]. The results of that study sparked the initiation of the phase I trial. The outcome
of this trial will be interesting as it only investigates the effect of inhaled azacitidine,
not in combination with other therapies, which as a single-agent therapy has so far
been unsuccessful. A caveat for the use of inhaled therapies in lung cancer is that
between 30 and 40% of patients will have systemic metastases at the time of clinical
diagnosis [123]. Logically, a therapy localized to the lungs will then need to be
combined with a more systemic one.
5 Conclusions and Future Directions
Progress has been made in the chemotherapy of lung cancer by employing drugs that
influence the reversible posttranslational and post-replicative modifications of proteins and DNA, respectively. However, optimum treatment regimens with such
drugs still need to be defined, and it is clear that mostly a combination with another
drug is required. In that sense the triple therapy of a HDACi, a DNMTi, and an
immune checkpoint inhibitor is an interesting approach that is currently being
investigated. Additionally, other influencers of PTMs, like inhibitors of KDMs, are
in clinical trials for lung cancer [121]. It is to be expected that in the future an even
broader range of compounds that influence the state of PTMs will be studied in
combination therapies for lung cancer.
The results of the studies in lung cancer are highly relevant to other lung diseases
like asthma and COPD, because one way to view the airway remodeling observed in
asthma and COPD is to compare it to benign tumor growth. For instance, in both
cases cell proliferation is out of control, and tissue boundaries are weakened.
Therefore, as in lung cancer therapy, using drugs that regain control of tissue
proliferation and architecture might be promising in asthma and COPD. Yet, as
mentioned in this chapter, the study of HDACi and other influencers of PTMs in
these diseases is still in the proof-of-principle stage. The initial in vivo preclinical
studies are nonetheless promising, especially in the case of HDACi. In mouse
models of asthma and COPD, application of several HDAC inhibitors has shown
to result in a broad range of beneficial effects. Local administration of HDACi at
Acetylation and Methylation in Asthma, COPD, and Lung Cancer
445