Therapeutic Targeting of Carbonic Anhydrases in Cancer

The metabolic adaptation of solid tumours generates regions of hypoxia and acidosis that promote malignant progression, invasion and therapy resistance. Carbonic anhydrases (CAs), particularly the transmembrane isoforms IX and XII, catalyse the reversible hydration of CO₂ to bicarbonate and protons, thereby modulating intracellular and extracellular pH. Upregulation of these isoforms under hypoxic conditions facilitates tumour cell survival by maintaining a favourable intracellular pH and acidifying the peritumoural space, which in turn enhances invasive potential and impairs immune surveillance. Therapeutic strategies aim to disrupt this pH-regulatory axis through selective inhibition of tumour-associated CAs. Approaches include small molecule inhibitors that coordinate to the active-site zinc, monoclonal antibodies that block enzymatic and non-catalytic functions, and combination regimens that exploit altered pH dynamics to improve drug delivery. Early clinical evaluation of lead compounds has demonstrated manageable safety profiles and preliminary antitumour activity, validating CAs as promising targets for adjuvant and combination therapies across a range of solid malignancies.

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Therapeutic Targeting of Carbonic Anhydrases in Cancer publication trend

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Technical terms

Carbonic anhydrase (CA): Metalloenzyme that catalyses the reversible conversion of carbon dioxide and water into bicarbonate and protons, central to pH homeostasis.

Isoform: Distinct variant of an enzyme arising from different genes or post-translational modifications, exemplified by CA IX and CA XII in tumours.

Hypoxia: Reduced oxygen availability in tissues, a hallmark of solid tumours that drives transcriptional upregulation of CA IX.

Tumour microenvironment: Complex milieu surrounding cancer cells, including gradients of oxygen, nutrients and pH that influence tumour behaviour.

Small molecule inhibitor: Low-molecular-weight compound designed to bind the active site of an enzyme and prevent its catalytic activity.

Monoclonal antibody: Highly specific immune protein engineered to bind and neutralise a target antigen, such as the extracellular domain of CA IX.

pH regulation: Control of acidity (proton concentration) within cells and their surroundings, critical for enzyme function and cell viability.

References

1. The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond. Cancer and Metastasis Reviews (2019).
2. Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites (2017).
3. Recent Developments in Targeting Carbonic Anhydrase IX for Cancer Therapeutics. Oncotarget (2012).
4. Carbonic Anhydrases: Role in pH Control and Cancer. Metabolites (2018).
5. Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors. Frontiers in Physiology (2014).