P=N/A, N=82, Completed, Novartis Pharmaceuticals

P1, N=3, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=23 --> 3

P2, N=64, Completed, University of Sydney | Active, not recruiting --> Completed

The disease later relapsed as high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-MYC/BCL2), still harbouring the BRAF mutation. Complete remission was achieved with Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisone, but the double-hit lymphoma relapsed 14 months later.This case illustrates sequential transformation from FL to BRAF-mutated HDS with excellent response to BRAF/MEK inhibition, followed by evolution into HGBCL-MYC/BCL2 responding transiently to immunochemotherapy, emphasising the value of repeated histological and molecular reassessment in FL evolution.

P1, N=267, Recruiting, Pfizer | Trial completion date: Aug 2030 --> Oct 2029 | Trial primary completion date: Feb 2029 --> Apr 2028

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.

Notably, we discover that RAF265, a compound already approved by the FDA, effectively inhibits USP10 activity, leading to decreased SCD1 expression and lipogenesis, which then suppresses tumor growth and enhances ferroptosis in both in vitro and in vivo models of HNSCC. Collectively, these results underscore the critical role of the E2F4/USP10/SCD1 pathway in modulating ferroptosis and driving HNSCC progression, suggesting that targeting this axis with RAF265 may offer a promising strategy for therapeutic intervention in this malignancy.

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.

Screening for drugs also revealed AKT1, TP53, and PIK3R4 as druggable hubs, and many drugs (e.g., Everolimus, Dabrafenib, Trabectedin) showing high-affinity interactions. The study discovers new prognostic markers (ATG4A, GABARAPL2, GAPDH) and druggable targets, which could lead to better risk stratification and smarter drug repurposing. While restricted to in silico analyses, the integrative approach provides a basis for subsequent laboratory confirmation and translational development.

Whilst the link between LCH and several haematological malignancies is documented, the mechanism is still unclear. In this case, the LCH most likely developed from an already abnormal myeloid compartment and highlights the need for clinical vigilance and appropriate investigation, where effective treatments for these conditions exist.