Pre-clinical evaluation of the aldehyde dehydrogenase 1A3 isoform as potential therapeutic target in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a fatal asbestos-associated malignancy of the lung pleura. MPM is a tumor with poor prognosis, characterized by a long latency period and a life expectancy of 11-12 months after diagnosis. Few treatment options exist for MPM patients, which unfortunately have a low response rate to the first line chemotherapy (cisplatin and pemetrexed combination). Recent advances have led the FDA (Food and Drug Administration) to approve two immunotherapy agents (ipilimumab and nivolumab) as a frontline treatment option for patients with unresectable MPM. Nevertheless, the identification of MPM patients that can benefit is far to be elucidated. Given the high resistance of this tumor to drugs approved up to now, continued research focused on identifying new targeted therapies and personalized approaches is critical. With the hope to improve the therapeutic efficacy of cisplatin in MPM patients, during my phD work I was involved in the biological evaluation of new four cisplatin-based prodrugs conjugated with PARP1 inhibitors. In the research of novel molecular targets in MPMs I focused my attention on the ALDH1A subfamily of enzymes that comprises isoforms ALDH1A1, ALDH1A2, and ALDH1A3, that irreversibly convert retinaldehyde to retinoic acid, and it is critical for detoxification of endogenous and exogenous aldehyde substrates to their corresponding carboxylic acids. We demonstrated that the inhibition of ALDH1A3, through an ALDH1A3 selective inhibitor (NR6), causes an accumulation of toxic aldehydes, in particular of MDA (malondialdehyde), responsible of DNA damage as demonstrated by the increase of the expression of yH2AX. Moreover, NR6 induces a cell growth arrest and a state of senescence with increased expression of CDKN2A (encoding p16ink4a) and IL-6 (interleukin 6). In MPM cells carrying CDKN2A deletion or in which CDKN2A expression has been silenced, NR6 induces apoptotic cell death as evidenced by the proteolytic cleavage of PARP-1 and the increased expression of BBC3 and BCL2L11. Moreover, we demonstrated that NR6 causes a marked reduction in the expression of IL-8 and significantly reduces the recruitment of neutrophils.