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Tumor Discovery HIF1α treatments in renal cell carcinoma

rates of Grade 3 and 4 AEs as those receiving sunitinib. Rapamycin, an mTOR inhibitor, decreases HIF1-α
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Cabozantinib was approved by the FDA in 2017 as the first- stabilization and transcriptional activity in hypoxic cancer
line treatment for advanced RCC. In a trial that compared cells. Temsirolimus, a single-agent mTOR inhibitor, has
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cabozantinib to sunitinib in patients with metastatic been FDA-approved since 2007 for first-line treatment of
ccRCC, cabozantinib had a longer PFS (8.2 months vs. advanced RCC with poor prognosis. It has demonstrated
5.6 months) and a significantly higher overall response improved PFS (3.8 vs. 1.9 months), OS (10.9 vs. 7.3 months),
rate (33% vs. 12%). The incidence of Grade 3 or 4 AEs and ORR (8.6% vs. 4.8%) compared to IFN-α treatment.
was similar between the two groups. Among patients In addition, it resulted in fewer Grade 3 or 4 toxicities
receiving cabozantinib, the most common Grade 3 or 4 compared to IFN-α (67% vs. 78%). 1,36,41 Common AE with
AEs were HTN (28%), diarrhea (10%), palmar-plantar temsirolimus includes asthenia, rash, anemia, nausea,
erythrodysesthesia (8%), and fatigue (6%). Tivozanib dyspnea, diarrhea, peripheral edema, hyperlipidemia, and
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was approved for advanced RCC after two or more prior hyperglycemia. Everolimus, another mTOR inhibitor,
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systemic therapies. Compared with sorafenib, tivozanib was FDA-approved 2 years after temsirolimus for RCC
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demonstrated improved PFS (11.9 vs. 9.1 months) and treatment following VEGF-targeted therapy failure. 1,21,41
comparable OS (29.3 vs. 28.8 months) and ORR (33.1% In a study of patients with metastatic RCC progression
vs. 23.3%) but lower rates of Grade 3 and 4 AEs (61% on VEGFR TKI, everolimus prolonged PFS (14.6 vs.
vs. 70%). Further, 4% of the patients on tivozanib had to 5.5 months) and OS (25.5 vs. 17.5 months) compared to
discontinue treatment due to toxicities compared with placebo. The study also showed improved ORR (43% vs.
5% of those on sorafenib. The most common side effects 6%) in the everolimus arm. Despite prolonged survival,
of tivozanib are HTN, diarrhea, dysphonia, and palmar- patients on everolimus had more AE/toxicities than the
plantar erythrodysesthesia. HTN (27%) and fatigue (5%) placebo arm (71% vs. 50%). Motzer et al. found that
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were the most common Grade 3 or 4 toxicities reported anemia (12%), dyspnea (8%), hypertriglyceridemia (8%),
in patients on tivozanib. Lenvatinib plus pembrolizumab, and hyperglycemia (10%) are the most common Grade 3
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an immunotherapy, was approved by the FDA as the or 4 AE in patients on everolimus. 43
first-line therapy for advanced RCC in 2021. Compared
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with sunitinib, the combination therapy of lenvatinib and 3.4. Hsp90 inhibitors
pembrolizumab had greater PFS (23.9 vs. 9.2 months) The accumulation of stabilized HIF1-α in the nucleus
and ORR (71% vs. 36%) but a higher rate of Grade 3 activates HIF signaling. Heat shock protein 90 (Hsp90), a
and 4 toxicities (82.4% vs. 71.8%). The most common chaperone molecule, ensures correct folding and protects
AEs associated with lenvatinib and pembrolizumab were HIF1-α from degradation. 40,44 Disruption of this association
diarrhea, HTN, hypothyroidism, decreased appetite, and leads to ubiquitination and proteasomal degradation of
fatigue. The most common Grade 3 or 4 toxicities for HIF1-α. 45,46 Studies have shown that Hsp90 inhibitors
the combination therapy were diarrhea, HTN, elevated lower HIF1-α protein levels regardless of the VHL status
lipase, and hypertriglyceridemia. A comparison of FDA- of the cells. Further, investigation of these drugs could lead
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approved treatments for RCC is outlined in Table 1. VEGF to more effective treatments against RCC. 44,45
inhibitors provide many options for first-line treatment of
RCC and initially have great results but patients commonly 3.5. HIF2-α inhibitors
develop resistance and must switch to a different type of HIF2-α is a major point of focus in research on RCC
therapy. 21 treatment and has emerged as a promising therapeutic
target, including upstream proteins that regulate the
3.3. mTOR inhibitors concentration of HIF2-α. At present, there is one FDA-
Indirect inhibitors of HIF1-α may also target upstream approved HIF2-α inhibitor. Belzutifan was approved
molecules to reduce its expression. Normally, VHL controls for use in 2021 and has been used to treat tumors
HIF1-α expression, but in cases of mutated VHL, as in associated with VHL syndrome, including RCC, as an
RCC, this regulation fails. mTOR activation increases alternative to surgery for solid tumors. This drug has
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HIF1-α expression and regulates cellular metabolism, demonstrated effectiveness in treating RCC in patients
growth, proliferation, and angiogenesis. 37,38 mTOR complex with VHL syndrome with an ORR of 49% and a 96% PFS at
1and mTOR complex 2 control HIF1-α expression; thus, 24 months. The most common AEs for belzutifan include
inhibiting these complexes limit HIF1-α accumulation anemia, fatigue, headache, and dizziness. Although not
and block the G1-S cell cycle transition. 38,39 Besides yet approved for sporadic RCC, studies are underway
promoting HIF1-α expression, mTOR stabilizes HIF1-α, to determine its efficacy for tumors other than those
allowing its nuclear translocation and accumulation. associated with VHL syndrome. 48

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