Abstract：
BACKGROUND: Aberrant DNA repair pathways contribute to malignant transformation or disease progression and the acquisition of drug resistance in multiple myeloma (MM); therefore, these pathways could be therapeutically exploited. Ribonucleotide reductase (RNR) is the rate-limiting enzyme for the biosynthesis of deoxyribonucleotides (dNTPs), which are essential for DNA replication and DNA damage repair. In this study, we explored the efficacy of the novel RNR inhibitor, 4-hydroxysalicylanilide (HDS), in myeloma cells and xenograft model. In addition, we assessed the clinical activity and safety of HDS in patients with MM.
METHODS: We applied bioinformatic, genetic, and pharmacological approaches to demonstrate that HDS was an RNR inhibitor that directly bound to RNR subunit M2 (RRM2). The activity of HDS alone or in synergy with standard treatments was evaluated in vitro and in vivo. We also initiated a phase I clinical trial of single-agent HDS in MM patients (ClinicalTrials.gov: NCT03670173) to assess safety and efficacy.
RESULTS: HDS inhibited the activity of RNR by directly targeting RRM2. HDS decreased the RNR-mediated dNTP synthesis and concomitantly inhibited DNA damage repair, resulting in the accumulation of endogenous unrepaired DNA double-strand breaks (DSBs), thus inhibiting MM cell proliferation and inducing apoptosis. Moreover, HDS overcame the protective effects of IL-6, IGF-1 and bone marrow stromal cells (BMSCs) on MM cells. HDS prolonged survival in a MM xenograft model and induced synergistic anti-myeloma activity in combination with melphalan and bortezomib. HDS also showed a favorable safety profile and demonstrated clinical activity against MM.
CONCLUSIONS: Our study provides a rationale for the clinical evaluation of HDS as an anti-myeloma agent, either alone or in combination with standard treatments for MM.
BACKGROUND: ClinicalTrials.gov, NCT03670173, Registered 12 September 2018.
METHODS: We applied bioinformatic, genetic, and pharmacological approaches to demonstrate that HDS was an RNR inhibitor that directly bound to RNR subunit M2 (RRM2). The activity of HDS alone or in synergy with standard treatments was evaluated in vitro and in vivo. We also initiated a phase I clinical trial of single-agent HDS in MM patients (ClinicalTrials.gov: NCT03670173) to assess safety and efficacy.
RESULTS: HDS inhibited the activity of RNR by directly targeting RRM2. HDS decreased the RNR-mediated dNTP synthesis and concomitantly inhibited DNA damage repair, resulting in the accumulation of endogenous unrepaired DNA double-strand breaks (DSBs), thus inhibiting MM cell proliferation and inducing apoptosis. Moreover, HDS overcame the protective effects of IL-6, IGF-1 and bone marrow stromal cells (BMSCs) on MM cells. HDS prolonged survival in a MM xenograft model and induced synergistic anti-myeloma activity in combination with melphalan and bortezomib. HDS also showed a favorable safety profile and demonstrated clinical activity against MM.
CONCLUSIONS: Our study provides a rationale for the clinical evaluation of HDS as an anti-myeloma agent, either alone or in combination with standard treatments for MM.
BACKGROUND: ClinicalTrials.gov, NCT03670173, Registered 12 September 2018.
摘要：
背景：异常的DNA修复途径有助于多发性骨髓瘤（MM）的恶性转化或疾病进展以及耐药性的获得；因此，这些途径可以进行治疗。核糖核苷酸还原酶（RNR）是脱氧核糖核苷酸（dNTP）生物合成的限速酶，对DNA复制和DNA损伤修复至关重要。在这项研究中,我们探索了新型RNR抑制剂的疗效，4-羟基水杨酰苯胺(HDS),在骨髓瘤细胞和异种移植模型中。此外,我们评估了MM患者HDS的临床活性和安全性。
方法：我们应用了生物信息学，遗传,和药理学方法证明HDS是直接与RNR亚基M2（RRM2）结合的RNR抑制剂。在体外和体内评价单独的或与标准处理协同的HDS的活性。我们还启动了MM患者单药HDS的I期临床试验（ClinicalTrials.gov：NCT03670173），以评估安全性和有效性。
结果：HDS通过直接靶向RRM2抑制RNR的活性。HDS降低RNR介导的dNTP合成,同时抑制DNA损伤修复,导致内源性未修复的DNA双链断裂（DSB）的积累，从而抑制MM细胞增殖并诱导细胞凋亡。此外，HDS克服了IL-6，IGF-1和骨髓基质细胞（BMSCs）对MM细胞的保护作用。HDS与美法仑和硼替佐米组合在MM异种移植模型中延长存活并诱导协同抗骨髓瘤活性。HDS还显示出良好的安全性，并证明了针对MM的临床活性。
结论：我们的研究为HDS作为抗骨髓瘤药物的临床评估提供了理论基础。单独或与MM的标准治疗组合。
背景：ClinicalTrials.gov，NCT03670173，2018年9月12日注册。
方法：我们应用了生物信息学，遗传,和药理学方法证明HDS是直接与RNR亚基M2（RRM2）结合的RNR抑制剂。在体外和体内评价单独的或与标准处理协同的HDS的活性。我们还启动了MM患者单药HDS的I期临床试验（ClinicalTrials.gov：NCT03670173），以评估安全性和有效性。
结果：HDS通过直接靶向RRM2抑制RNR的活性。HDS降低RNR介导的dNTP合成,同时抑制DNA损伤修复,导致内源性未修复的DNA双链断裂（DSB）的积累，从而抑制MM细胞增殖并诱导细胞凋亡。此外，HDS克服了IL-6，IGF-1和骨髓基质细胞（BMSCs）对MM细胞的保护作用。HDS与美法仑和硼替佐米组合在MM异种移植模型中延长存活并诱导协同抗骨髓瘤活性。HDS还显示出良好的安全性，并证明了针对MM的临床活性。
结论：我们的研究为HDS作为抗骨髓瘤药物的临床评估提供了理论基础。单独或与MM的标准治疗组合。
背景：ClinicalTrials.gov，NCT03670173，2018年9月12日注册。
