Belzutifan led to radiographic improvement in pulmonary metastases and symptoms, while other lesions remained stable. This suggests its potential therapeutic use in TFE3-rearranged renal cell carcinoma.

P2, N=355, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Jun 2029 --> Dec 2029 | Trial primary completion date: Jun 2029 --> Dec 2029

Casdatifan has shown promising clinical activity in the ARC-20 ccRCC platform study, both as monotherapy and in combination with the VEGFR tyrosine kinase inhibitor (TKI) cabozantinib. Currently, casdatifan is being evaluated in a Phase 3 trial in combination with cabozantinib (NCT07011719) in patients with advanced ccRCC.

Both in vitro and in vivo, the HIF-2α inhibitor belzutifan (PT2977) effectively suppressed this signaling axis and reversed the tumor-promoting effects caused by PARP1 overexpression. Collectively, our findings elucidate a critical role for the HIF-2α/TRIB3/PARP1 axis in ccRCC progression, revealing potential therapeutic targets and rational combination strategies for this disease.

In contrast, degradation-governed release from PSiNPs sustained the availability of belzutifan and trametinib in aqueous physiological medium for more than 10 days supporting prolonged intracellular drug exposure when combined with the established cellular internalization of this carrier system. Sustained dual inhibition enhanced cytotoxicity and promoted immunogenic remodeling in MCPyV-negative Merkel cell carcinoma models, including increased calreticulin exposure and reduced PD-L1 expression. These findings identify release synchronization as a critical biomaterial design parameter for combination cancer therapy.

The clinical success of HIF-2α-specific allosteric inhibitors underscores the importance of exploiting unique structural vulnerabilities, whereas the lack of analogous pockets in HIF-1α necessitates alternative approaches. We propose that durable suppression of hypoxia-driven pathology will likely require integration of isoform-specific targeting with translational control mechanisms that decouple HIF signaling from generalized cytotoxic stress.

P1, N=29, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed | N=52 --> 29 | Trial completion date: Jul 2026 --> Apr 2026 | Trial primary completion date: Jul 2026 --> Apr 2026

P2, N=78, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

HIF is not involved in the CCNT1/BHLHE40/Tim8-Tim13 interaction, and neither genetic HIF-1β knockout nor pharmacological HIF-2α inhibition (belzutifan) eliminates BHLHE40 expression. Finally, BHLHE40 depletion compromises the proliferation of 786-O clear cell renal carcinoma cells, which constitutively express HIF-2α and hypoxia-responsive genes. Together, these findings reveal a partially HIF-independent regulatory axis, in which Tim8-Tim13 complexes and BHLHE40 modulate P-TEFb activity in the transcriptional response to hypoxia.

Therefore, this study evaluated the effects of sodium selenite (SS), selenium-enriched yeast (SY), selenomethionine (SM), and nano-selenium (NS) on gut microbiota and their metabolites, intestinal antioxidant capacity, immune response, and gut morphology in broilers, and investigated the potential molecular mechanisms by which Se influences intestinal function in broilers...Supplementation with SY increased ileal concentrations of secretory immunoglobulin A by 74.87% and interleukin-10 (IL-10) by 54.90%, enhanced ileal activities of total superoxide dismutase (T-SOD) by 123.55% and catalase by 197.20%, and elevated cecal acetate by 35.67% and total short-chain fatty acids (SCFAs) by 28.78%, as well as ileal ursodeoxycholic acid concentration by 154.05% (P < 0.05)...In summary, SS and SY improved intestinal antioxidant and immune functions in broilers, whereas SY and NS enhanced cecal SCFAs production. Moreover, Se supplementation modulated the cecal microbial community in broilers.

P2, N=150, Not yet recruiting, Vall d'Hebron Institute of Oncology

P2/3, N=154, Not yet recruiting, Merck Sharp & Dohme LLC