Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Jul 27

PMID 35884358

Authors

Paul C McDonald

Shawn C Chafe

Claudiu T Supuran

Shoukat Dedhar

Affiliations

Soon will be listed here.

Abstract

Carbonic Anhydrase IX (CAIX) is a major metabolic effector of tumor hypoxia and regulates intra- and extracellular pH and acidosis. Significant advances have been made recently in the development of therapeutic targeting of CAIX. These approaches include antibody-based immunotherapy, as well as use of antibodies to deliver toxic and radioactive payloads. In addition, a large number of small molecule inhibitors which inhibit the enzymatic activity of CAIX have been described. In this commentary, we highlight the current status of strategies targeting CAIX in both the pre-clinical and clinical space, and discuss future perspectives that leverage inhibition of CAIX in combination with additional targeted therapies to enable effective, durable approaches for cancer therapy.

Citing Articles

The Antiepileptic Drug Levetiracetam Inhibits Carbonic Anhydrase: and Studies on Catalytically Active Human Isoforms.

Cutarella L, Mori M, Supuran C ACS Med Chem Lett. 2024; 15(12):2133-2139.

PMID: 39691524 PMC: 11647675. DOI: 10.1021/acsmedchemlett.4c00380.

Exploring the Polypharmacological Potential of PCI-27483: A Selective Inhibitor of Carbonic Anhydrases IX and XII.

DAgostino I, Bonardi A, Ferraroni M, Gratteri P, Angeli A, Supuran C ACS Med Chem Lett. 2024; 15(11):2042-2045.

PMID: 39563799 PMC: 11571002. DOI: 10.1021/acsmedchemlett.4c00443.

Establishment of a Prognostic Model for Pancreatic Cancer Based on Hypoxia-Related Genes.

Wu Y, Zhou J, Kou Q, Sun L, Ma Y, Yang T Technol Cancer Res Treat. 2024; 23:15330338241288687.

PMID: 39431298 PMC: 11504279. DOI: 10.1177/15330338241288687.

Isocoumarins incorporating chalcone moieties act as isoform selective tumor-associated carbonic anhydrase inhibitors.

Onyilmaz M, Koca M, Ammara A, Degirmenci M, Supuran C Future Med Chem. 2024; 16(13):1347-1355.

PMID: 39109432 PMC: 11318696. DOI: 10.1080/17568919.2024.2350875.

Design and synthesis of chromene-1,2,3-triazole benzene sulfonamide hybrids as potent carbonic anhydrase-IX inhibitors against prostate cancer.

Albelwi F, Nafie M, Albujuq N, Hourani W, Aljuhani A, Darwish K RSC Med Chem. 2024; 15(7):2440-2461.

PMID: 39026656 PMC: 11253856. DOI: 10.1039/d4md00302k.

References

Chafe S, McDonald P, Saberi S, Nemirovsky O, Venkateswaran G, Burugu S . Targeting Hypoxia-Induced Carbonic Anhydrase IX Enhances Immune-Checkpoint Blockade Locally and Systemically. Cancer Immunol Res. 2019; 7(7):1064-1078. DOI: 10.1158/2326-6066.CIR-18-0657. View

Pacchiano F, Carta F, McDonald P, Lou Y, Vullo D, Scozzafava A . Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem. 2011; 54(6):1896-902. DOI: 10.1021/jm101541x. View

Debreova M, Csaderova L, Burikova M, Lukacikova L, Kajanova I, Sedlakova O . CAIX Regulates Invadopodia Formation through Both a pH-Dependent Mechanism and Interplay with Actin Regulatory Proteins. Int J Mol Sci. 2019; 20(11). PMC: 6600150. DOI: 10.3390/ijms20112745. View

McDonald P, Swayampakula M, Dedhar S . Coordinated Regulation of Metabolic Transporters and Migration/Invasion by Carbonic Anhydrase IX. Metabolites. 2018; 8(1). PMC: 5876009. DOI: 10.3390/metabo8010020. View

Murri-Plesko M, Hulikova A, Oosterwijk E, Scott A, Zortea A, Harris A . Antibody inhibiting enzymatic activity of tumour-associated carbonic anhydrase isoform IX. Eur J Pharmacol. 2011; 657(1-3):173-83. DOI: 10.1016/j.ejphar.2011.01.063. View

Ames S, Andring J, McKenna R, Becker H . CAIX forms a transport metabolon with monocarboxylate transporters in human breast cancer cells. Oncogene. 2019; 39(8):1710-1723. DOI: 10.1038/s41388-019-1098-6. View

Supuran C . Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov. 2008; 7(2):168-81. DOI: 10.1038/nrd2467. View

Sarnella A, Ferrara Y, Auletta L, Albanese S, Cerchia L, Alterio V . Inhibition of carbonic anhydrases IX/XII by SLC-0111 boosts cisplatin effects in hampering head and neck squamous carcinoma cell growth and invasion. J Exp Clin Cancer Res. 2022; 41(1):122. PMC: 8976345. DOI: 10.1186/s13046-022-02345-x. View

McDonald P, Chia S, Bedard P, Chu Q, Lyle M, Tang L . A Phase 1 Study of SLC-0111, a Novel Inhibitor of Carbonic Anhydrase IX, in Patients With Advanced Solid Tumors. Am J Clin Oncol. 2020; 43(7):484-490. PMC: 7323835. DOI: 10.1097/COC.0000000000000691. View

10.

Nocentini A, Capasso C, Supuran C . Small-molecule CD73 inhibitors for the immunotherapy of cancer: a patent and literature review (2017-present). Expert Opin Ther Pat. 2021; 31(10):867-876. DOI: 10.1080/13543776.2021.1923694. View

11.

McDonald P, Winum J, Supuran C, Dedhar S . Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget. 2012; 3(1):84-97. PMC: 3292895. DOI: 10.18632/oncotarget.422. View

12.

Kalinin S, Malkova A, Sharonova T, Sharoyko V, Bunev A, Supuran C . Carbonic Anhydrase IX Inhibitors as Candidates for Combination Therapy of Solid Tumors. Int J Mol Sci. 2021; 22(24). PMC: 8705727. DOI: 10.3390/ijms222413405. View

13.

Lee S, Namasivayam V, Boshta N, Perotti A, Mirza S, Bua S . Discovery of potent nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) inhibitors with ancillary carbonic anhydrase inhibition for cancer (immuno)therapy. RSC Med Chem. 2021; 12(7):1187-1206. PMC: 8292979. DOI: 10.1039/d1md00117e. View

14.

Chamie K, Donin N, Klopfer P, Bevan P, Fall B, Wilhelm O . Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma: The ARISER Randomized Clinical Trial. JAMA Oncol. 2016; 3(7):913-920. PMC: 5824229. DOI: 10.1001/jamaoncol.2016.4419. View

15.

Ciccone V, Filippelli A, Angeli A, Supuran C, Morbidelli L . Pharmacological Inhibition of CA-IX Impairs Tumor Cell Proliferation, Migration and Invasiveness. Int J Mol Sci. 2020; 21(8). PMC: 7215745. DOI: 10.3390/ijms21082983. View

16.

Sarnella A, DAvino G, Hill B, Alterio V, Winum J, Supuran C . A Novel Inhibitor of Carbonic Anhydrases Prevents Hypoxia-Induced TNBC Cell Plasticity. Int J Mol Sci. 2020; 21(21). PMC: 7664880. DOI: 10.3390/ijms21218405. View

17.

Wang Y, Buck A, Grimaud M, Culhane A, Kodangattil S, Razimbaud C . Anti-CAIX BBζ CAR4/8 T cells exhibit superior efficacy in a ccRCC mouse model. Mol Ther Oncolytics. 2022; 24:385-399. PMC: 8792103. DOI: 10.1016/j.omto.2021.12.019. View

18.

Lenferink A, McDonald P, Cantin C, Grothe S, Gosselin M, Baardsnes J . Isolation and characterization of monoclonal antibodies against human carbonic anhydrase-IX. MAbs. 2021; 13(1):1999194. PMC: 8632296. DOI: 10.1080/19420862.2021.1999194. View

19.

Damgaci S, Enriquez-Navas P, Pilon-Thomas S, Guvenis A, Gillies R, Ibrahim-Hashim A . Immunotherapy on acid: opportunities and challenges. Eur J Clin Nutr. 2020; 74(Suppl 1):3-6. PMC: 7777416. DOI: 10.1038/s41430-020-0683-7. View

20.

Kciuk M, Gielecinska A, Mujwar S, Mojzych M, Marciniak B, Drozda R . Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies. J Enzyme Inhib Med Chem. 2022; 37(1):1278-1298. PMC: 9090362. DOI: 10.1080/14756366.2022.2052868. View