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Tumor Discovery

REVIEW ARTICLE
Hypoxia-inducible factor-1α inhibition in renal

cell carcinoma

Kinsey Morey , Santosh Nimkar 1 , and Samir Dalia *
1
2
1 College of Osteopathic Medicine, Joplin Campus, Kansas City University, Joplin, Missouri,
United States of America
2 Department of Medical Oncology, Mercy Hospital, Joplin, Missouri, United States of America

Abstract

The tumorigenesis of clear cell renal cell carcinoma (ccRCC), an aggressive variant
of renal cell carcinoma (RCC), is primarily attributable to the mutational inactivation
of the Von Hippel–Lindau (VHL) gene. This mutation causes VHL syndrome, which is
associated with tumor growth in various body parts, including the brain, spinal cord,
eyes, adrenal glands, pancreas, kidney, and reproductive tract. RCC is the leading cause
of death in patients with VHL syndrome. The VHL gene acts as a tumor suppressor that
prevents the proliferation of various oncogenes by controlling the hypoxia-inducible
factor (HIF). The HIF pathway is directly linked to the control of metabolic adaptation,
cell proliferation, migration, angiogenesis, and apoptosis, which, in turn, is linked
to ccRCC tumorigenesis. Consequently, many treatments have been developed to
directly or indirectly inhibit HIF1α. Direct inhibition of HIF-1α was briefly explored
but has not yet resulted in any treatment strategy approved by the Food and
Drug Administration. Most prevalent are the indirect inhibitors targeting vascular
endothelial growth factor receptors (VEGFR), the mammalian target of rapamycin
*Corresponding author: (mTOR), and heat shock protein 90 (Hsp90). The VEGFR inhibitor category has the
Samir Dalia
(samir.dalia@mercy.net) most FDA-approved drugs as they have been proven to be the most efficacious and
safe early on. Thus, VEGFR inhibitors, along with mTOR inhibitors, have become the
Citation: Morey K, Nimkar S, mainstay in RCC treatment. Most recently, therapies targeting HIF-2α inhibition have
Dalia S. Hypoxia-inducible
factor-1α inhibition in renal gained traction with FDA approval, whereas emerging therapies targeting direct
cell carcinoma. Tumor Discov. inhibition of hsp90 have shown promise.
2024;3(4):4346.
doi: 10.36922/td.4346
Received: July 27, 2024 Keywords: Renal cell carcinoma; HIF-1α; HIF-2α; HIF-1α inhibitor; HIF-2α inhibitor; VEGF
inhibitor; mTOR inhibitor
Accepted: September 10, 2024
Published Online: October 8, 2024
Copyright: © 2024 Author(s).
This is an Open-Access article 1. Introduction
distributed under the terms of the
Creative Commons Attribution Renal cell carcinoma (RCC) originates from the kidney epithelium and constitutes
License, permitting distribution, approximately 2% of all cancers worldwide. Common risk factors include smoking,
and reproduction in any medium,
provided the original work is obesity, and hypertension (HTN), with approximately 2% being hereditary. The classic
properly cited. triad of RCC symptoms includes hematuria, abdominal pain, and a palpable mass,
Publisher’s Note: AccScience but most cases remain asymptomatic until advanced stages. Over 50% of RCCs are
Publishing remains neutral with discovered incidentally, and 20 – 30% are metastatic at diagnosis. Metastases commonly
regard to jurisdictional claims in
published maps and institutional occur in the lungs, bones, liver, and brain. Primary treatment is surgical resection,
affiliations. followed by medical therapy for locally advanced or metastatic disease as recurrence can

Volume 3 Issue 4 (2024) 1 doi: 10.36922/td.4346