Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors

ABSTRACT

Introduction: Hypoxic tumors overexpress two carbonic anhydrases (CA, EC 4.2.1.1), CA IX and XII, involved in complex processes connected to tumorigenesis (pH regulation, metabolism, invasion, and dissemination of the tumor). The biochemical rationale behind these processes is orchestrated by the transcription factor hypoxia inducible factor 1 (HIF-1).

Areas covered: CA IX and XII have been validated as antitumor/antimetastatic drug targets and may be used for imaging hypoxic tumors. Many CA inhibitors (CAIs) belonging to the sulfonamide, coumarin and sulfocoumarin classes selectively inhibit these two isoforms. CA IX/XII inhibitors inhibit the growth of primary tumors and the formation of metastases and deplete the cancer stem cell population, alone or in combination with other agents. These are three beneficial antitumor mechanisms that make them unique among anticancer drugs available.

Expert opinion: Indisulam entered clinical trials as an antitumor sulfonamide; it progressed to Phase II trials but was terminated in 2016. However, SLC-0111, a sulfonamide CA IX/XII inhibitor 1, recently completed a successful Phase I clinical trial for the treatment of advanced, metastatic solid tumors. This compound is now in Phase Ib/II clinical trials and is being assessed as a monotherapy or in combination with other agents such as gemcitabine. CA IX/XII inhibitors are synergistic with other anticancer agents (cisplatin, proton pump inhibitors, doxorubicin, temozolamide) and are a versatile, emerging class of antitumor drugs.

KEYWORDS:

• Carbonic anhydrase inhibitors
• hypoxic tumors
• sulfonamide
• treatment
• imaging
• SLC-0111
• carbonic anhydrases

Article highlights

• Carbonic anhydrases (CAs) catalyze the interconversion between CO₂ and bicarbonate with release of a proton and are involved in pH regulation and metabolism.

• Two CA isoforms, CA IX and XII, are overexpressed in many tumors being found in limited concentrations in normal tissues.

• CA IX/XII were recently validated as antitumor, theranostic targets, their inhibition impairing the growth of primary tumors, metastases and reducing the number of cancer stem cells.

• CA IX/XII-selective inhibitors were developed, which showed a significant antitumor activity in vitro and in animal models of hypoxic tumors, also offering the possibility for imaging tumors.

• Synergistic effects of the CA IX/XII inhibitors with other anticancer agents (cisplatin, proton pump inhibitors, doxorubicin, temozolamide, etc.) were observed.

• SLC-0111, a sulfonamide CA IX/XII inhibitor, is in Phase Ib/II clinical trials as an antitumor drug for the management of advanced, hypoxic solid tumors.

This box summarizes key points contained in the article.

Declaration of interest

The author is one of the discoverers of SLC-0111. The author have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer was involved in the discovery of the SLC-0111 CAIX inhibitor discussed in this article. Other peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.