OT-82

OT-82 treatment of HLRCC xenograft tumors in vivo inhibited glycolytic flux as demonstrated by reduced lactate/pyruvate ratio in hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging experiments. Overall, our data define NAMPT inhibition as a potential therapeutic approach for FH-deficient HLRCC-associated renal cell carcinoma.

Lastly, treatment of RS-PDX mice with the combination of PI3Ki and OT-82 results in significant inhibition of tumor growth, with evidence of in vivo activation of apoptosis. Collectively, these data highlight a novel application for NAMPT inhibitors in combination with BTKi or PI3Ki in aggressive lymphomas.

RMS is highly vulnerable to NAMPT inhibition. These findings underscore the need for further clinical study of this class of agents for this malignancy.

NAMPT inhibition with OT-82 was highly effective in decreasing RMS proliferation and impairing glucose metabolism both in vitro and in vivo. Given these results, there is a critical need for further clinical study of this class of agents for RMS.

A few notable NAMPT specific inhibitors which have been produced include FK866, CHS828, and OT-82. This paper examines a number of cancer treatment methods which target NAMPT, including the usage of individual inhibitors, pharmacological combinations, dual inhibitors, and ADCs, all of which have demonstrated promising experimental or clinical results. We intend to contribute further ideas regarding the usage and development of NAMPT inhibitors in clinical therapy to advance the field of research on this intriguing target.

In vitro and in vivo efficacy of OT-82 suggest that targeting NAD+ metabolism through NAMPT inhibition may be a promising approach for the treatment of RMS.

As NAMPT inhibitors (NAMPTi) we used both FK866 and OT-82, which are validated small molecules. These results highlight a crosstalk between BCR signalling and NAMPT/sirtuin axis in RS models, showing the increased efficacy of the dual targeting (i.e., PI3K-δ/γ and NAMPT), and supporting this novel and promising therapeutic strategy for the treatment of RS patients.

In addition, OT-82 enhanced the efficacy of the established drugs cytarabine and dasatinib and, as a single agent, showed similar efficacy as an induction-type regimen combining three drugs used to treat pediatric ALL. OT-82 sensitivity was associated with the occurrence of mutations in major DNA damage response genes, while OT-82 resistance was characterized by high expression levels of CD38. In conclusion, our study provides evidence that OT-82, as a single agent, and in combination with established drugs, is a promising new therapeutic strategy for a broad spectrum of high-risk pediatric ALL for which improved therapies are urgently needed.

Furthermore, combining low-dose OT-82 with low doses of agents augmenting DNA damage demonstrated enhanced antitumor activity in vitro and in vivo. Thus, OT-82 treatment represents a potential novel targeted approach for the clinical treatment of EWS.