Animal models clearly show extraordinary translational potential for PPARγ
ligands to serve as either preventative therapies or cotreatments for lung malignancies. Recent clinical studies also suggest favorable outcomes in lung cancer patients treated with PPARγ
ligands. In a clinical study encompassing patients with diabetes, lung cancer occurrence in patients receiving TZD therapy was decreased by 33% compared to patients not taking a TZD [96
]. Notably, the decrease in lung carcinomas was still evident after confounding factors (i.e., age and race/ethnicity) were accounted for. At the present time, clinical trials are underway to investigate the effectiveness of TZDs in the prevention and/or treatment of lung cancer, either alone, or in combination with other chemotherapies. It is important to note that TZDs show both PPARγ
-dependent and -independent modes of action and further exploration of their mechanism of action is needed to elucidate their specific targets. CDDO and its derivatives have proapoptotic and antiproliferative effects on cancer cells in vitro
and are currently being investigated in phase 2 clinical trials for treatment of cancer [97
]. Further studies are required to determine if CDDO-Me will also be useful as a myelosuppressive agent in combination with chemotherapies.
Currently, there are no PPARγ
ligands in clinical trial for fibrotic lung diseases. However, there is evidence in other organ systems suggesting that PPARγ
ligands may have antifibrotic potential in human lung fibrosis. Intriguingly, kidney remodeling is a frequent complication of diabetes, and improvements in renal function have been noted in patients with type II diabetes treated with TZDs [98
]. The use of TZDs in clinical therapy may be limited by undesirable side effects. However, unlike diabetes, which can often be managed with alternate therapies, there are no current treatments for IPF and the median survival time after diagnosis is only 2-3 years, which may shift the risk-benefit assessment in favor of use.
In addition to lung cancer and fibrosis, pioglitazone and rosiglitazone are in ongoing clinical trials for asthma (e.g., NCT01134835 and NCT00614874), cystic fibrosis (e.g., NCT00322868 and NCT01060566), pulmonary hypertension (e.g., NCT00825266 and NCT00006071), and pulmonary arterial disease (e.g., NCT00153166 and NCT00064727). These studies will evaluate whether the in vitro anti-inflammatory effects of PPARγ ligands can be translated to improved patient outcomes.
Current PPARγ ligands act via both PPARγ-dependent and -independent mechanisms, and the impact of both pathways must be considered in evaluating their efficacy in animal models and clinical trials. However, the existence of PPARγ-independent effects creates the potential for development of novel non-PPAR-based therapies that access the independent pathways uncovered by PPARγ ligands. In this event, currently available PPARγ ligands with strong PPAR-independent effects, such as 15d-PGJ2 and CDDO, may play a more important role as probes for novel disease modifying pathways than as direct clinical treatments, paving the way for new molecules that target critical pathways (such as Akt, FAK, ERK, and JNK) without also activating PPARγ.
It is interesting to note that some of the PPARγ
-independent effects of PPARγ
ligands are mediated by modulating the phosphorylation status of key regulatory enzymes such as Akt, FAK, ERK, and JNK. Imatinib mesylate (Gleevec), a broad-spectrum tyrosine kinase inhibitor currently approved to treat some cancers, has been tested in several small open-label trials in systemic sclerosis, a fibrosing disease that often involves the lung. In some studies, imatinib improved lung function and reduced skin contraction, although the number of adverse effects was high [100
]. However, in a randomized, placebo-controlled trial of patients with mild to moderate IPF, imatinib did not significantly reduce disease progression [29
]. These studies demonstrate the clinical potential as well as limitation of antikinase treatments in lung fibrosis and encourage further exploration of the non-PPAR molecular targets of PPARγ