Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma.

Purpose: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, CLPP activators which reduce OXPHOS indirectly and have demonstrated safety in patients. Experimental Design: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201, ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic effects in vivo in UM liver metastasis models. Results: CLPP expression was confirmed in primary and mUM patient samples. ONC201/212 treatment of UM cell lines in vitro decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis. ONC212 increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models. Conclusion: Imipridones are a promising strategy for further testing and development in mUM.

Advances in Diagnosis and Treatment for Leptomeningeal Disease in Melanoma.

PURPOSE OF REVIEW: Melanoma has one of the highest incidences of causing leptomeningeal disease (LMD) among solid tumors. LMD patients have very poor prognosis with a dismal survival despite aggressive management. In this article, we review the current approaches in the management of patients with LMD secondary to melanoma, including updates in diagnosis, treatment, up-to-date clinical studies, and future directions. RECENT FINDINGS: Cerebrospinal fluid (CSF) cytology remains the gold standard for diagnosis, and alternatively, MRI based on clinical presentation can be used. Other approaches such as "liquid biopsies" that detect circulating tumor cells and cell-free DNA have the potential to considerably enhance the diagnosis of LMD from melanoma. As for treatment options, several systemic therapies, involving systemic targeted and immunotherapies have evolved that showed to have possible benefit in LMD patients. Intrathecal chemotherapy, cellular therapy, and immunotherapy are currently under evaluation in Phase I/II clinical trials. In addition, new radiation therapy approaches such as proton cranial-spinal irradiation (CSI) are currently under investigation. LMD management still remains challenging. Future studies are critical to elucidate the pathophysiology of LMD in order to develop new urgently needed diagnostic tools and therapies. Clinical trials ought to be expanded to include patients with LMD. Future clinical studies should also integrate tissue interrogation, scientifically designed therapies, and aggressive, early intervention in patients with suspected LMD.