P1, N=56, Active, not recruiting, University of Auckland, New Zealand | Trial completion date: Mar 2024 --> Aug 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

Thus, therapeutic strategies targeting pVHL-HIF signalling have been explored in ccRCC, culminating in the successful development of HIF2α-specific antagonists such as belzutifan (PT2977), an FDA-approved drug to treat VHL-associated diseases including advanced-stage ccRCC. An increased understanding of hypoxia signalling in kidney cancer came from the discovery of novel VHL protein (pVHL) targets, and mechanisms of synthetic lethality with VHL mutations. These breakthroughs can pave the way for the development of innovative and potent combination therapies in kidney cancer.

P2, N=730, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Aug 2026 --> Mar 2027 | Trial primary completion date: Aug 2026 --> Mar 2027

P1, N=14, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

P3, N=1800, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

Several clinical trials are currently ongoing, which should help in identifying this promising drug's role in RCC and beyond. This review summarizes the history, pharmacology and clinical evidence for belzutifan use to date, and also explores unanswered questions as they relate to this novel therapeutic agent.

P1, N=14, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

To determine the mechanism, pancreatic cancer cells were treated with selenomethionine or RSL3, an inhibitor of glutathione peroxidase 4 (GPx4). RSL3 treatment inhibited GPx4 activity and increased lipid peroxidation. Differences in oxidative stress may play a role in radioprotecting normal cells while radiosensitizing pancreatic cancer cells when treated with P-AscH-.

P2, N=0, Withdrawn, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=30 --> 0 | Not yet recruiting --> Withdrawn

P1, N=40, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2025 --> Feb 2025 | Trial primary completion date: Jul 2025 --> Feb 2025

The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs...MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations.

This study evaluated the effects of selenium nanoparticles (SeNP), selenite, and selenomethionine (SeMet) on the growth, antioxidant capacity, selenium content, selenium speciation, and meat quality of grass carp...Furthermore, as an additive, 0.3 mg/kg SeNP significantly improved the flesh quality of grass carp by reducing crude fat and heavy metal content, as well as increasing the levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the ratio of n-3/n-6 polyunsaturated fatty acid (PUFA). In summary, SeNP is the most suitable additive for producing selenium-enriched fish.

Despite both patients experiencing a pulmonary crisis with respiratory compromise, their rapid response to belzutifan further emphasizes its potential utility in cases involving pulmonary or visceral crises. This report contributes valuable insights into the treatment landscape for advanced ccRCC with somatic VHL mutations.

Separation of diastereomeric mixtures at two different stages of the synthesis proved advantageous in ease of separation. The X-ray structure of belzutifan was determined.

In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC.

P1, N=17, Completed, Merck Sharp & Dohme LLC | Recruiting --> Completed

P1, N=40, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

Collectively, SeMet inhibits the growth of PDTC in a dose-dependent manner through LncRNA NONMMUT014201/miR-6963-5p/Srprb signal pathway, thus suggesting that SeMet might be a potential drug for PDTC treatment.

P1, N=56, Active, not recruiting, University of Auckland, New Zealand

P1, N=40, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=180 --> 40

In this exploratory, post-hoc analysis of LITESPARK-004, data suggests that administration of ESA did not adversely impact overall drug exposure or efficacy of belzutifan in pts with VHL disease associated RCC, CNS hemangioblastomas, and pNETs. Clinical trial information: NCT03401788.

Enrollment for this study is currently ongoing. Clinical trial information: NCT02861573.

The EcoToxChip project includes RNA-sequencing data from experiments involving model (Japanese quail, fathead minnow, African clawed frog) and ecological (double-crested cormorant, rainbow trout, northern leopard frog) species, at multiple life stages (whole embryo and adult), exposed to eight chemicals of environmental concern known to perturb a wide range of biological systems (ethinyl estradiol, hexabromocyclododecane, lead, selenomethionine, 17β trenbolone, chlorpyrifos, fluoxetine, and benzo[a]pyrene). The most common enriched pathways were metabolic pathways, biosynthesis of cofactors and biosynthesis of secondary metabolites, and chemical carcinogenesis, drug metabolism and metabolism of xenobiotics by Cytochrome P450. The RNA-sequencing database presented here may be used by the research community for multiple purposes, including for example, cross-species investigations, in depth analyses of a particular test compound, and transcriptomic meta-analyses.

Belzutifan appears to be an effective and safe treatment for CNS hemangioblastoma in VHL patients. Further clinical trials to assess the long-term effectiveness of the medication are required.

P1/2, N=128, Recruiting, NiKang Therapeutics, Inc. | N=98 --> 128

Surgical removal is considered the first line of therapy, although belzutifan, a HIF-2α inhibitor, is currently being tested as a potential therapy. Early screening with plasma metanephrines may assist in identifying PPGLs in patients with CCHD.

After a median follow-up of 41.2 months, belzutifan monotherapy demonstrated durable antitumor activity in patients with advanced ccRCC and acceptable safety.

P1, N=56, Active, not recruiting, University of Auckland, New Zealand | Not yet recruiting --> Active, not recruiting

PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.

Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting.

4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6-17 months). All patients had radiographic response to therapy after a median of 3 months (2-5 months), with maximal response to therapy after a median of 8 months (3-17 months).

In the LITESPARK-005 and -003 trials, the HIF-2α inhibitor looks effective in advanced clear-cell renal cell carcinoma, both as monotherapy and in combination with VEGFR tyrosine kinase inhibitors. The results favor expanding belzutifan's use beyond von Hippel-Lindau disease-associated cancers, its only current indication.

Combined with the reported PHD2.HIFα-ODD structures and biochemical studies, the results inform on the different PHD.HIFα-ODD binding modes and the potential effects of clinically observed mutations in HIFα and PHD2 genes. They may help enable new therapeutic avenues, including PHD isoform-selective inhibitors and sequestration of HIF2α by the PHDs for ccRCC treatment.

The neuroprotective effect of organic Se compounds, selenomethionine (SeMet) and Ebselen, was evaluated through cell viability tests, acetylcholinesterase and antioxidant enzyme activities, and detection of reactive oxygen species (ROS). Cell differentiation induced by RA and BDNF exposure was effective, showing characteristics of neuronal cells, and pointing to a promising model of AD. Ebselen showed a protective effect, but more studies are needed to identify the mechanism of action.

Moreover, investigations of the mechanism revealed that SM might exert antioxidant effects on HO-induced LMHs by activating the Nrf2 pathway and enhancing the activities of major antioxidant selenoenzymes downstream. These findings provide evidence for the effectiveness of SM on ameliorating HO-induced oxidative impairment and suggest SM has the potential to be used in the prevention or adjuvant treatment of oxidative-related impairment in poultry feeds.

Our findings show that SeMet inhibits the proliferation of HNSCC cells and promotes their apoptosis by targeting TopBP1/ATR and TCAB1 signaling. SeMet is a potential method for HNSCC treatment.

Early trials of belzutifan indicate encouraging efficacy and good tolerability in sporadic mRCC as well. The potential inclusion of belzutifan and other HIF-2α inhibitors into the mRCC treatment armamentarium either as a single agent or as combination therapy would be a welcome addition for patients with mRCC.

Currently, widespread in-vitro and in-vivo research is focusing on targeting HIF with drugs that have already been approved for use by the FDA, such as belzutifan, in renal cell carcinoma...Although HIF-targeting agents have been investigated for over a decade, their use in therapy-resistant cancers remains relevant and should be explored further. In addition, the use of naturally occurring HIF inhibitors should be considered as an add-on therapy for the currently used regimens.

In this model dual UGT2B17 and CYP2C19 poor metabolizers (PM) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve (AUC) compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in overall- and sub-populations for belzutifan labeling.

Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management.