Evolution of the HIF targeted therapy in clear cell renal cell carcinoma

Borivoj Golijanin; Kamil Malshy; Sari Khaleel; Galina Lagos; Ali Amin; Liang Cheng; Dragan Golijanin; Anthony Mega

doi:10.1016/j.ctrv.2023.102645

Evolution of the HIF targeted therapy in clear cell renal cell carcinoma

Cancer Treat Rev. 2023 Dec:121:102645. doi: 10.1016/j.ctrv.2023.102645. Epub 2023 Oct 15.

Authors

Borivoj Golijanin¹, Kamil Malshy², Sari Khaleel², Galina Lagos³, Ali Amin⁴, Liang Cheng⁴, Dragan Golijanin², Anthony Mega³

Affiliations

¹ The Minimally Invasive Urology Institute at The Miriam Hospital, Division of Urology, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States. Electronic address: bgolijanin.med@proton.me.
² The Minimally Invasive Urology Institute at The Miriam Hospital, Division of Urology, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States.
³ Lifespan Cancer Institute, Department of Hematology and Oncology, The Miriam Hospital, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States.
⁴ Department of Pathology and Laboratory Medicine, The Miriam Hospital, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States.

PMID: 37879247
DOI: 10.1016/j.ctrv.2023.102645

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, affecting hundreds of thousands of people worldwide and can affect people of any age. The pathogenesis of ccRCC is most commonly due to biallelic loss of the tumor suppressor gene VHL. VHL is the recognition subunit of an E3-ubiquitin-ligase-complex essential for degradation of the hypoxia-inducible factors (HIF) 1α and 2α. Dysfunctional degradation of HIF results in overaccumulation, which is particularly concerning with the HIF2α subunit. This leads to nuclear translocation, dimerization, and transactivation of numerous HIF-regulated genes responsible for cell survival and proliferation in ccRCC. FDA-approved therapies for RCC have primarily focused on targeting downstream effectors of HIF, then incorporated immunotherapeutics, and now, novel approaches are moving back to HIF with a focus on interfering with upstream targets. This review summarizes the role of HIF in the pathogenesis of ccRCC, novel HIF2α-focused therapeutic approaches, and opportunities for ccRCC treatment.

Keywords: Clear cell; HIF; Metastasis; Renal cell carcinoma; Targeted therapy; VHL.

Publication types

Review

MeSH terms

Carcinoma, Renal Cell* / drug therapy
Carcinoma, Renal Cell* / genetics
Carcinoma, Renal Cell* / metabolism
Cell Line, Tumor
Humans
Kidney Neoplasms* / drug therapy
Kidney Neoplasms* / genetics
Kidney Neoplasms* / metabolism
Von Hippel-Lindau Tumor Suppressor Protein / genetics
Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

Von Hippel-Lindau Tumor Suppressor Protein