Metastatic Uveal Melanoma

NBM-BMX: A Precision Therapy for Uveal Melanoma

Mutations in the BAP1 gene prevent normal protection of p53, a key tumor suppressor. At the same time, overexpression of HDAC8 blocks the transcription of p53 protein, allowing cancer cells to grow unchecked. NBM-BMX is a selective HDAC8 inhibitor designed to restore this critical pathway. In a Phase I trial, one patient with uveal melanoma achieved complete remission and has remained disease-free for more than 18 months. This represents a single-patient observation and requires further scientific validation. These results support the continued development of NBM-BMX as a precision treatment for UM patients with high HDAC8 expression. Under FDA regulations, positive Phase II data could enable accelerated approval.

P53 is a tumor suppressor protein with acetyl groups and ubiquitin proteins attached. When BAP1 is normal, it cuts off ubiquitin (UB) to activate p53, mutated BAP1 loses this deubiquitinating function and in the meantime, HDAC8 is highly increased, leading to deacetylate the acetyl groups on p53. This can be blocked by NBM-BMX to restore the tumor suppressing activities of p53.

The ubiquitin–proteasome system (UPS) is the principal protein quality-control and degradation machinery in eukaryotic cells, responsible for eliminating misfolded, damaged, or superfluous proteins

Target proteins are first tagged with ubiquitin (a small polypeptide), and subsequently degraded by specific proteases. Through this energy-dependent process, cells selectively degrade proteins in a highly specific manner when they are no longer needed.