Merkel Cell Carcinoma

We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53/MDM2 negative feedback loop. KTX-049 was >100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling...Acquired resistance was strongly associated with acquisition of TP53 mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT TP53 MCC.

Understanding the interplay between viral status, genomic burden, and the immune landscape is essential for overcoming ICI resistance. Rational combination strategies, particularly ICI plus radiation or epigenetic modulators to restore MHC-I expression, offer pathways to improve outcomes in resistant disease.

P2, N=135, Recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Not yet recruiting --> Recruiting

Importantly, while sT-Ag alone induces partial MCC-associated gene expression, suppression of p53 is required for sT-Ag to induce neuroendocrine lineage transdifferentiation in the hair follicle. Cumulatively, these studies enhance our knowledge of MCC biology and establish a de novo MCC tumorigenesis model in a tractable immunocompetent system that will be invaluable for further advancements in the field.

P3, N=101, Active, not recruiting, University of Washington | Trial primary completion date: Apr 2026 --> Jan 2029

P=N/A, N=35, Active, not recruiting, University Hospital, Tours | Not yet recruiting --> Active, not recruiting | N=150 --> 35 | Trial completion date: Sep 2023 --> Dec 2026 | Trial primary completion date: Sep 2021 --> Dec 2025

However, further research is needed to explore its functions in other cancers and clarify its molecular mechanisms. Our review synthesizes current knowledge on CXorf67's biological significance, particularly in epigenetics and DNA damage, and its implications in oncogenesis.

This case underscores the importance of integrating cytologic, histopathologic, and molecular features when evaluating thyroid nodules with overlapping characteristics. Recognition of this rare coexistence prevents misclassification and unnecessary aggressive management, ensuring accurate diagnosis and optimal patient outcomes.

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.

P=N/A, N=20, Active, not recruiting, University of Wisconsin, Madison | Recruiting --> Active, not recruiting

Our findings support the role of MCPyV in MCC formation and suggest its involvement in the transcriptional regulation of DDR genes, which may influence tumor progression. Understanding the molecular interplay between MCPyV and the DDR may guide future research into plausible novel diagnostic and therapeutic strategies for virus-induced tumors.

P1, N=36, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting --> Recruiting