A Preclinical Study on the Rescue of Normal Tissue by Nicotinic Acid in High-Dose Treatment with APO866, a Specific Nicotinamide Phosphoribosyltransferase Inhibitor

Abstract

Inhibitor of nicotinamide phosphoribosyltransferase APO866 is a promising cancer drug currently in phase II clinical trials in oncology. Here, we present a strategy for increasing the therapeutic potential of APO866 through the rescue of normal tissues by coadministration of nicotinic acid (Vitamin B 3 ). We examined the toxicity profile of APO866 in B6D2F1 mice and the effect of oral administration of nicotinic acid on tissue toxicity. Nicotinic acid (50 mg/kg) protects mice from death and severe toxicity from an APO866 dose (60 mg/kg) four times the monotherapy maximum tolerated dose (15 mg/kg). In a panel of six cancer cell lines, we find that three (including ML-2 cells) are protected by nicotinic acid in vitro, whereas the cytotoxicity of APO866 remains unaffected in the remaining three (including A2780 cells). A selective biomarker for the protection by nicotinic acid was subsequently identified by quantitative RT-PCR. The expression of nicotinic acid phosphoribosyltransferase is low in the cell lines not rescued from APO866 by nicotinic acid compared with protected cell lines. The findings in cell lines translated into xenograft models in which the combination of 50 mg/kg nicotinic acid and 50 mg/kg APO866 in mouse xenografts of A2780 cells increased life span by >3-fold compared with standard treatment of 15 mg/kg, and the effect of APO866 was clearly decreased when using the same treatment paradigm in ML-2 xenografts. In conclusion, the combination of high doses of APO866 with rescue by nicotinic acid may significantly increase the therapeutic potential in a subset of cancers with low expression of nicotinic acid phosphoribosyltransferase. Mol Cancer Ther; 9(6); 1609-17. ©2010 AACR.

Loss of NAPRT1 Expression by Tumor-Specific Promoter Methylation Provides a Novel Predictive Biomarker for NAMPT Inhibitors

“…Previous studies have indicated that NAPRT1 is required for nicotinic acid rescue (16,17). We wanted to test this observation in a larger panel of cell lines and identify additional determinants of nicotinic acid rescue across cancer cell lines from a diverse range of tissue types.…”

“…1A). Addition of nicotinic acid to the media or food allows this pathway to generate sufficient levels of NAD to mitigate the cytotoxic effects of a NAMPT inhibitor in cultured cells and animal rodents (15)(16)(17) as well as in human megakaryocytes (18). Interestingly, some cancers do not express NAPRT1 (19), rendering this pathway nonfunctional.…”

DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade

“…An FK866 administration schedule (i.p. injection twice a day, 4 days on, 3 days off) was selected based on previous efficacy-tolerability studies (19). Although FK866 delayed tumor growth in all populations, only ERCC1-KO models displayed a significant difference in tumor volumes between the FK866 and vehicle groups ( Figure 5, B-D).…”

“…Our findings indicate that ERCC1-deficient tumors may respond to NAMPT inhibitors at lower doses than their ERCC1-proficient counterparts, which may enable reaching antitumor activity while avoiding excessive toxicities in selected populations thanks to a favorable therapeutic window. In addition, by analogy with the folate rescue used for high-dose methotrexate administration, whether the tolerability of these drugs might be improved by adding sequential vitamin B3 or NMN administration (14,19) might deserve clinical evaluation. Similarly, alternative schedules that use more frequent administration at lower doses might be worth exploring in order to achieve similar drug exposure and avoid peak-related, dose-limiting toxicity.…”

Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Coadministration

“…The de novo biosynthesis of NAD þ from tryptophan mainly occurs in the liver and under certain stressed conditions (4). Therefore, the NAM salvage pathway represents the major route to NAD þ biosynthesis in the mammals (9)(10)(11). In cancer cells, NAMPT plays a crucial role in several physiological processes including energy generation, reductive biosynthesis, mitochondrial function, and the response to oxidative stress (1,(12)(13)(14).…”