Tarrant Jacqueline M, Dhawan Preeti, Singh Jatinder, Zabka Tanja S, Clarke Emer, DosSantos Garry, Dragovich Peter S, Sampath Deepak, Lin Tori, McCray Bobbi, La Nghi, Nguyen Trung, Kauss Ariel, Dambach Donna, Misner Dinah L, Diaz Dolores, Uppal Hirdesh
Department of Safety Assessment, Genentech Inc. , South San Francisco, CA , USA .
Toxicol Mech Methods. 2015 Mar;25(3):201-11. doi: 10.3109/15376516.2015.1014080. Epub 2015 Apr 20.
Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in glycolysis and is a key molecule involved in maintaining cellular energy metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of an important salvage pathway in which nicotinamide is recycled into NAD. NAMPT is up-regulated in many types of cancer and NAMPT inhibitors (NAMPTi) have potential therapeutic benefit in cancer by impairing tumor metabolism. Clinical trials with NAMPTi APO-866 and GMX-1778, however, failed to reach projected efficacious exposures due to dose-limiting thrombocytopenia. We evaluated preclinical models for thrombocytopenia that could be used in candidate drug selection and risk mitigation strategies for NAMPTi-related toxicity. Rats treated with a suite of structurally diverse and potent NAMPTi at maximum tolerated doses had decreased reticulocyte and lymphocyte counts, but no thrombocytopenia. We therefore evaluated and qualified a human colony forming unit-megakaryocyte (CFU-MK) as in vitro predictive model of NAMPTi-induced MK toxicity and thrombocytopenia. We further demonstrate that the MK toxicity is on-target based on the evidence that nicotinic acid (NA), which is converted to NAD via a NAMPT-independent pathway, can mitigate NAMPTi toxicity to human CFU-MK in vitro and was also protective for the hematotoxicity in rats in vivo. Finally, assessment of CFU-MK and human platelet bioenergetics and function show that NAMPTi was toxic to MK and not platelets, which is consistent with the clinically observed time-course of thrombocytopenia.
烟酰胺腺嘌呤二核苷酸（NAD）是糖酵解中一种必需的辅酶，是维持细胞能量代谢的关键分子。烟酰胺磷酸核糖基转移酶（NAMPT）催化一条重要补救途径的限速步骤，该途径可将烟酰胺再循环为NAD。NAMPT在多种癌症中上调，NAMPT抑制剂（NAMPTi）通过损害肿瘤代谢在癌症治疗中具有潜在益处。然而，由于剂量限制性血小板减少，NAMPTi APO - 866和GMX - 1778的临床试验未能达到预期的有效暴露量。我们评估了可用于候选药物选择和NAMPTi相关毒性风险缓解策略的血小板减少症临床前模型。用一系列结构多样且有效的NAMPTi以最大耐受剂量治疗的大鼠，其网织红细胞和淋巴细胞计数减少，但未出现血小板减少。因此，我们评估并验证了人巨核细胞集落形成单位（CFU - MK）作为NAMPTi诱导的巨核细胞毒性和血小板减少症的体外预测模型。我们进一步证明，基于以下证据，巨核细胞毒性是靶向性的：烟酸（NA）通过一条不依赖NAMPT的途径转化为NAD，它可以减轻NAMPTi对人CFU - MK的体外毒性，并且在体内对大鼠的血液毒性也具有保护作用。最后，对CFU - MK和人血小板生物能量学及功能的评估表明，NAMPTi对巨核细胞有毒性，而对血小板无毒性，这与临床上观察到的血小板减少症的时间进程一致。
