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Tumor Discovery HIF1α treatments in renal cell carcinoma

garnered significant attention for its promising results approved RCC treatments in this category. The first drug
in treating RCC and other cancers. The primary focus of in this category to receive FDA approval was sorafenib
these studies is on inhibiting the accumulation of HIF1-α in 2005. Sorafenib is a tyrosine kinase inhibitor (TKI)
or its downstream products. Direct HIF1-α inhibitors of the VEGF receptor (VEGFR) that has been shown to
target the expression or function of HIF molecules by delay progression and help preserve the patient’s quality
inhibiting mRNA expression, HIF protein synthesis, of life. In a trial study, sorafenib resulted in an OS that
dimerization of the alpha and beta subunits, DNA binding was 3.4 months longer than the placebo and an overall
with HIF, and HIF’s transcriptional activities. Indirect response that was 8% higher in patients with advanced
HIF1-α inhibitors regulate molecules in the upstream or RCC. Adverse events (AE) occurred in 13% of the patients,
downstream pathways affecting HIF. HIF2-α is another necessitating dose reduction. Some common AEs and
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therapeutic target for RCC. Overexpression of HIF2-α toxicities of sorafenib include diarrhea (43%), rash
promotes angiogenesis and tumor invasion, similar to (40%), hand-foot syndrome (30%), and HTN (17%). 17-19
HIF1-α, but complete loss of HIF2-α can also contribute The next drug to receive FDA approval was sunitinib in
to oncogenesis. Therefore, direct inhibitors of HIF2-α, 2006, another VEGFR inhibitor similar to sorafenib, that
which reduce its cellular concentration, are an appealing replaced interferon-alpha (IFN-α) as the standard of care
treatment for RCC. At present, HIF2-α inhibitors are used for RCC treatment. Compared with IFN-α, which has
only in patients with VHL syndrome but show promise as an average progression-free survival (PFS) of 5 months,
an effective treatment for sporadic RCC. 7 sunitinib has an average PFS of 11 months. In patients
with advanced RCC, sunitinib had an overall response rate
2. Methods that was 25% higher than IFN-α. 20-22 Patients receiving
The initial search for articles was conducted through this therapy commonly presented with thrombocytopenia,
Google Scholar and PubMed using the keywords “Renal leukopenia, neutropenia, fatigue, diarrhea, vomiting, and
Cell Carcinoma,” “RCC,” “ccRCC,” “HIF1-α,” “HIF1-α HTN. Considering the AEs and toxicities, 32% of the
inhibitor,” “hypoxia-inducible factor,” “VEGF inhibitor,” patients receiving sunitinib required dose reduction, and
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and “VHL gene.” Studies on drugs that inhibited HIF1-α 38% needed a break in treatment. Bevacizumab, an anti-
and HIF2-α directly or indirectly and those on RCC were VEGF antibody that targets and inhibits VEGFRs, was
included in the study. The selected studies were further approved by the FDA in 2009. Compared with IFN-α alone,
narrowed down to include studies on the treatment of bevacizumab in combination with IFN-α had a longer PFS
locally advanced or metastatic RCC. Studies on HIF1-α (10.2 vs. 5.4 months) and higher objective tumor response
inhibitors not targeting RCC, those conducted >2 years rates (31% vs. 13%). 17,24 Common Grade 3 or 4 AEs for
before FDA approval, and those not in English were bevacizumab include fatigue (35%), anorexia (17%),
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excluded from the study. proteinuria (13%), and HTN (9%). In 2009, pazopanib,
a VEGFR inhibitor, was approved by the FDA for the
3. Results treatment of metastatic RCC. Compared with sunitinib,
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pazopanib had a longer PFS (9.8 vs. 4.3 months) and OS
3.1. Direct HIF1-α inhibitors
(14.4 vs. 8.9 months) but had a higher rate of treatment
Direct inhibition of HIF1-α impacts the expression or discontinuation due to toxicities (3% vs. 1%). Common
function of HIF molecules and is a less common therapeutic side effects include aspartate transaminase (AST)/alanine
approach due to the numerous pathways controlled by HIF. transaminase (ALT) elevation, HTN, fatigue, anorexia,
At present, these therapies are not FDA-approved for RCC nausea, stomatitis, and diarrhea. The most common
treatment, but several studies have investigated these drugs Grade 3 or 4 AEs are leukopenia, neutropenia, and ALT
in combination with other approved treatments. These elevation. Axitinib is a second-generation VEGFR
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studies have shown promising results and could potentially inhibitor that was approved by the FDA in 2012 for the
be highly effective against RCC. 15,16 treatment of advanced RCC after one prior systemic therapy
failure. 21,28 When used for the treatment of advanced
3.2. VEGF inhibitors ccRCC, axitinib in combination with avelumab, an anti-

The most commonly targeted molecules for treatment are programmed death-ligand 1 antibody, showed antitumor
the upstream and downstream components of the HIF activity and a longer PFS of 13.8 months compared with
pathway that can indirectly inhibit HIF1-α. VEGF and 8.4 months for sunitinib. The most common Grade 3 or
20
15
VEGF receptor inhibitors are commonly used as targets 4 AEs for patients receiving axitinib with avelumab were
for RCC treatment due to its the highly vascularized HTN (24.4%), diarrhea (5.1%), and fatigue (3%). Patients
nature of these tumors. At present, there are eight FDA- receiving axitinib combined with avelumab had similar

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