P2, N=26, Active, not recruiting, University Health Network, Toronto | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

P2, N=10, Active, not recruiting, UNICANCER | Trial completion date: Mar 2026 --> Mar 2027

P2, N=7, Active, not recruiting, Northwestern University | Recruiting --> Active, not recruiting | N=43 --> 7 | Trial primary completion date: Jul 2028 --> May 2026

P2, N=86, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2026 --> Jun 2027 | Trial primary completion date: Sep 2026 --> Feb 2026

The cytotoxic effects of three MAPK pathway inhibitors (selumetinib, vemurafenib, dabrafenib) were assessed in ATC cell lines and xenograft models via viability assays and 18F-FDG PET/CT. Furthermore, MAPK pathway inhibitors increased radioiodine uptake in ATC cells. The MAPK pathway inhibitors enhance NIS function through two mechanisms: upregulation of NIS expression and increased ARF4-mediated NIS membrane transport.

Our results highlight that both hypoxia and therapeutic pressure modulate tumor progression in a complex, context-dependent manner.

Notably, δ-TT restored responsiveness to vemurafenib, indicating a synergistic interaction in resistant melanoma cells. Overall, these findings provide mechanistic evidence supporting a potential role for δ-TT as a modulator of drug response and support further investigation of δ-TT-based combination strategies to overcome therapeutic resistance in melanoma.

In contrast, compounds 16, 17, and 22 displayed marked cellular activity despite limited B-RAF inhibition, indicating potential contributions from alternative kinases or yet unidentified off-target mechanisms. The large DSF Tm shifts observed established the poorly exploited pyrimido[4,5-d]pyrimidines as interesting ATP mimetic scaffolds for kinase inhibitor development.

P2, N=43, Recruiting, Northwestern University | Trial completion date: Jul 2028 --> Jul 2030 | Trial primary completion date: Jul 2026 --> Jul 2028

Vemurafenib markedly inhibited HCC cell proliferation and metastasis, which was accompanied by a pronounced induction of apoptosis and G0/G1 phase cell-cycle arrest. At the signaling level, these cellular responses were linked to enhanced JNK activation and the suppression of AKT phosphorylation, suggesting that vemurafenib may serve as a potential therapeutic agent for HCC.

CST also reduced the viability and migration of Vemurafenib-resistant A375 cells, accompanied by the downregulation of multiple resistance-associated genes...Mechanistically, CST downregulates key pro-tumorigenic and pro-fibrotic signaling molecules, including LOXL2, PDGFRB, CCN2, and DDIT4, which are associated with extracellular-matrix remodeling, growth factor signaling, and cellular stress adaptation. These findings identify CST as a novel regulator of tumor survival and metastatic potential, supporting its therapeutic potential as a peptide-based anti-cancer agent.

P1/2, N=12, Active, not recruiting, Instytut Matki I Dziecka | Recruiting --> Active, not recruiting