A New Vista of Aldehyde Dehydrogenase 1A3 (ALDH1A3): New Specific Inhibitors and Activity-Based Probes Targeting ALDH1A3 Dependent Pathways in Glioblastoma, Mesothelioma and Other Cancers

Our plain-English summary of A New Vista of Aldehyde Dehydrogenase 1A3 (ALDH1A3): New Specific Inhibitors and Activity-Based Probes Targeting ALDH1A3 Dependent Pathways in Glioblastoma, Mesothelioma and Other Cancers, by L. Magrassi, G. Pinton, S. Luzzi, et al (Cancers, 2024).

The study

• Authors: L. Magrassi, G. Pinton, S. Luzzi, S. Comincini, A. Scravaglieri, V. Gigliotti, B.L. Bernardoni, I. D'Agostino, F. Juretich, C. La Motta, S. Garavaglia
• Journal: Cancers
• Published: 2024;16(13)
• Type of article: Review
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes necessary for the oxidation of all-trans or 9-cis retinal to retinoic acid (RA). Retinoic acid and its derivatives are important for normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. Moreover, in recent years, it has been demonstrated that ALDH1A members are also expressed and functional in several human cancers where their role is not limited to the synthesis of RA. Here, we review the current knowledge about ALDH1A3, one of the 1A isoforms, in cancers with an emphasis on two of the deadliest tumors that affect humans: glioblastoma multiforme and mesothelioma. In both tumors, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance, and invasiveness. We also review the recent attempts to develop both ALDH1A3-selective inhibitors for cancer therapy and ALDH1A3-specific fluorescent substrates for fluorescence-guided tumor resection.

In plain English

This article was a review, not a new study. The authors summarized published research on ALDH1A3, an enzyme involved in making retinoic acid, in human cancers. They focused on glioblastoma, a brain tumor, and pleural mesothelioma, which the review describes as caused by asbestos exposure. No asbestos exposure was studied. The review stated that in both tumors ALDH1A3 is considered a negative prognostic factor. It cited an earlier analysis of 84 pleural mesothelioma patients in the Cancer Genome Atlas database, which found high ALDH1A3 expression significantly associated with poorer prognosis. It also cited laboratory work in which mesothelioma cell lines treated with cisplatin and pemetrexed gave rise to drug-resistant cells with high ALDH1A3. The review described NR6, an experimental ALDH1A3 inhibitor that hindered the growth of mesothelioma cells grown as 3D spheroids in the laboratory. It also described fluorescent probes meant to mark tumor tissue during surgery. The authors stated that none of the new specific inhibitors had been extensively tested in preclinical models. They concluded that these tools now need testing in appropriate experimental models. Two authors hold a patent on an ALDH1A3 probe.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research
• Who was studied: No study population of its own. The review covers published laboratory, animal and patient-data research on ALDH1A3 in human cancers, with emphasis on glioblastoma and pleural mesothelioma.
• Exposure: No asbestos or fiber exposure was studied. The review states that pleural mesothelioma is caused by asbestos exposure. The topic is the enzyme ALDH1A3 and experimental compounds that inhibit it or label it.
• Main results:
  • The review reports that in glioblastoma and mesothelioma, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance and invasiveness.
  • The review cites an earlier analysis of the Cancer Genome Atlas (TCGA) database covering 84 pleural mesothelioma patients. In that analysis, high ALDH1A3 expression was significantly associated with poorer prognosis.
  • The review cites laboratory work in which stable and primary pleural mesothelioma cell lines treated with cisplatin and pemetrexed gave rise to drug-resistant cell subpopulations with high ALDH1A3 expression.
  • The review cites work by Boumya and colleagues. In that work, the selective ALDH1A3 inhibitor NR6 hindered the growth of ALDH1A3-positive pleural mesothelioma cells grown in the laboratory as 3D multicellular spheroids.
  • The review cites a multicenter phase II study in recurrent temozolomide-resistant glioblastoma. In that study, disulfiram, a non-selective ALDH inhibitor, was given with copper and showed no positive results.
  • The authors report from their own earlier work that a fluorescent probe they developed, Probe I, labeled experimental high-grade gliomas growing in the brains of mice.
• The authors' conclusion: The authors concluded that increased ALDH1A3 expression in glioblastoma and many other cancers has been confirmed by multiple approaches. They also concluded that the new ALDH1A3 inhibitors and fluorescent probes now need testing in appropriate experimental models to measure their activity and specificity in vivo.
• Limitations the authors state:
  • The authors state that none of the new specific ALDH1A3 inhibitors had yet been extensively tested in preclinical models.
  • The authors note that the widely used Aldefluor reagent is not specific to a single ALDH enzyme and can give false negative results.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

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