Iron deficiency impairs skeletal muscle regeneration by stabilizing HIF-2α in MuSC, inducing Rb1 RNA expression, and repressing E2F-dependent proliferation. Transient HIF-2α inhibition rescues MuSC proliferation and muscle repair under iron-deficient conditions, highlighting HIF-2α as a potential therapeutic target to counteract sarcopenia in aging and chronic diseases.

P2, N=160, Recruiting, IDEAYA Biosciences | N=82 --> 160 | Trial completion date: Jan 2029 --> Apr 2030 | Trial primary completion date: Jan 2026 --> Apr 2027

Drug sensitivity analysis identified compounds such as sotrastaurin (-10.2 kcal/mol), austocystin D (-9.7 kcal/mol), and tivozanib (-9.3 kcal/mol) as potentially effective inhibitors based on predicted binding affinity. Our integrative analysis highlights HTR1F as a potential biomarker associated with prognosis, immune modulation, and drug sensitivity across multiple cancer types. These findings provide a foundation for future experimental and clinical studies to explore HTR1F-targeted therapies.

P3, N=520, Recruiting, IDEAYA Biosciences | Not yet recruiting --> Recruiting | Trial completion date: Dec 2027 --> Mar 2031 | Trial primary completion date: May 2027 --> Oct 2030

Moreover, expression of a stable BCL2 mutant confers resistance to both FAKi+MEKi and FAKi+"RAF-MEK clamp" (avutometinib) treatment. Of direct translational relevance, we found that an approved BCL2 inhibitor (venetoclax) displays synergistic efficacy with FAK+MEK blockade and overcomes acquired resistance, including when combined with darovasertib, a dual PKC/PKN inhibitor limiting MEK and FAK signaling that is under clinical evaluation. Our findings suggest that resistance to FAKi+MEKi in UVM cells can be driven by an adaptive upregulation of the anti-apoptotic protein BCL2, and that, in turn, BCL2 inhibitors represent a promising precision-targeted strategy to overcome FAKi+MEKi treatment resistance and improve therapeutic outcomes.

When a sustained release formulation of polymeric microparticles (MP) delivering CCL22 (CCL22MP), was administered after cardiotoxin (CTx)-mediated muscle injury, significantly improved limb function was observed on days 3 and 5 post injury...Analysis of the local immune populations revealed augmented Treg concentrations, as well as increased myeloid derived suppressor cell and neutrophil frequency. These findings reveal that amplifying local Treg to damaged areas improves outcomes, thus offering a translationally promising approach after muscle injury.

Combination therapy using decoy oligonucleotides or the PRKCD inhibitor sotrastaurin with sorafenib synergistically inhibited HCC progression. Collectively, our findings reveal a non-canonical role of PHGDH in regulating mRNA metabolism and modulating mitophagy. Targeting the RNA-binding activity of PHGDH with decoy oligonucleotides represents a promising therapeutic strategy for HCC.

This localized approach may provide significant benefit for patients with limited extrahepatic spread. Future research should focus on optimizing these novel strategies-tebentafusp, darovasertib, melphalan, and combination therapies-and on expanding our understanding of UM's molecular drivers to enable the development of more effective, personalized treatments.

P3, N=520, Not yet recruiting, IDEAYA Biosciences

Thus, targeting the non-canonical WNT signalling pathway via combinatorial PKC and MAPK pathway inhibition is beneficial for therapy-resistant cutaneous melanoma combating tumour heterogeneity in vivo. With our study, we are providing an alternate treatment strategy we think is worth investigating as future clinical interventions in cutaneous melanoma.

This comprehensive analysis reveals key challenges in PKC drug development, including the need for enhanced selectivity and reduced off-target effects, while highlighting promising directions for future therapeutic development. Our findings provide a framework for designing next-generation PKC inhibitors with improved clinical potential.

Inhibitory drugs dexamethasone, dasatinib, and sotrastaurin prevented NK cell transition to an activated state and suppressed the expression of IFN-γ by NK cells, thus preventing IFN-γ mediated target cell transcriptomic response. In conclusion, we discovered that SMAC mimetics sensitize cancer cells to NK cell mediated killing, with potential clinical applications especially in patients with advanced phase CML.