| Program | Preclinical | Phase I | Phase Ib/Expansion | Phase II | Phase III |
|---|---|---|---|---|---|
| Metastatic Uveal Melanoma | |||||
NBM-BMX: A Precision Therapy for Uveal Melanoma
Restoration of the p53 Tumor-Suppressing Pathway
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. 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 removes ubiquitin (Ub) to activate p53. Mutated BAP1 loses this deubiquitinating function, and in the meantime, HDAC8 is highly increased, leading to deacetylation of the acetyl groups on p53.
Targeting HDAC8 to Reactivate p53 Function
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.
References (Key Publications)
- LaFave, L. M., et al.
Loss of BAP1 function leads to a dependency on HDAC8 activity in uveal melanoma.
Nature Medicine, 2015; 21(12): 1471–1479. - Miller, T. A., et al.
Synthetic lethal targeting of chromatin regulators in cancer.
Nature Reviews Cancer, 2016; 16(8): 491–503. - Deardorff, M. A., et al.
HDAC8 mutations disrupt cohesin acetylation and cause mitotic defects.
Nature, 2012; 489(7415): 313–317. - Biochimica et Biophysica Acta (BBA) – Reviews on Cancer.
Epigenetic dysregulation and therapeutic vulnerabilities in cancer.
Biochim Biophys Acta Rev Cancer, PMC, August 11, 2025. - Cancer Treatment Reviews.
Targeting epigenetic regulators in cancer therapy: current status and future directions.
Cancer Treat Rev, PMC, November 1, 2021.
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