Hogarty Michael D, Norris Murray D, Davis Kimberly, Liu Xueyuan, Evageliou Nicholas F, Hayes Candace S, Pawel Bruce, Guo Rong, Zhao Huaqing, Sekyere Eric, Keating Joanna, Thomas Wayne, Cheng Ngan Ching, Murray Jayne, Smith Janice, Sutton Rosemary, Venn Nicola, London Wendy B, Buxton Allen, Gilmour Susan K, Marshall Glenn M, Haber Michelle
Division of Oncology, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318, USA.
Cancer Res. 2008 Dec 1;68(23):9735-45. doi: 10.1158/0008-5472.CAN-07-6866.
Neuroblastoma is a frequently lethal childhood tumor in which MYC gene deregulation, commonly as MYCN amplification, portends poor outcome. Identifying the requisite biopathways downstream of MYC may provide therapeutic opportunities. We used transcriptome analyses to show that MYCN-amplified neuroblastomas have coordinately deregulated myriad polyamine enzymes (including ODC1, SRM, SMS, AMD1, OAZ2, and SMOX) to enhance polyamine biosynthesis. High-risk tumors without MYCN amplification also overexpress ODC1, the rate-limiting enzyme in polyamine biosynthesis, when compared with lower-risk tumors, suggesting that this pathway may be pivotal. Indeed, elevated ODC1 (independent of MYCN amplification) was associated with reduced survival in a large independent neuroblastoma cohort. As polyamines are essential for cell survival and linked to cancer progression, we studied polyamine antagonism to test for metabolic dependence on this pathway in neuroblastoma. The Odc inhibitor alpha-difluoromethylornithine (DFMO) inhibited neuroblast proliferation in vitro and suppressed oncogenesis in vivo. DFMO treatment of neuroblastoma-prone genetically engineered mice (TH-MYCN) extended tumor latency and survival in homozygous mice and prevented oncogenesis in hemizygous mice. In the latter, transient Odc ablation permanently prevented tumor onset consistent with a time-limited window for embryonal tumor initiation. Importantly, we show that DFMO augments antitumor efficacy of conventional cytotoxics in vivo. This work implicates polyamine biosynthesis as an arbiter of MYCN oncogenesis and shows initial efficacy for polyamine depletion strategies in neuroblastoma, a strategy that may have utility for this and other MYC-driven embryonal tumors.
神经母细胞瘤是一种常见的致命性儿童肿瘤，其中MYC基因失调，通常表现为MYCN扩增，预示着预后不良。确定MYC下游必需的生物途径可能会带来治疗机会。我们通过转录组分析表明，MYCN扩增的神经母细胞瘤协同失调了无数的多胺酶（包括ODC1、SRM、SMS、AMD1、OAZ2和SMOX），以增强多胺生物合成。与低风险肿瘤相比，无MYCN扩增的高风险肿瘤也过表达ODC1，即多胺生物合成中的限速酶，这表明该途径可能至关重要。事实上，在一个大型独立神经母细胞瘤队列中，ODC1升高（与MYCN扩增无关）与生存率降低相关。由于多胺对细胞存活至关重要且与癌症进展相关，我们研究了多胺拮抗作用，以测试神经母细胞瘤中该途径的代谢依赖性。Odc抑制剂α-二氟甲基鸟氨酸（DFMO）在体外抑制神经母细胞瘤增殖，在体内抑制肿瘤发生。用DFMO治疗易患神经母细胞瘤的基因工程小鼠（TH-MYCN），可延长纯合小鼠的肿瘤潜伏期和生存期，并预防半合子小鼠发生肿瘤。在后者中，短暂的Odc缺失可永久预防肿瘤发生，这与胚胎肿瘤起始的时间限制窗口一致。重要的是，我们表明DFMO在体内增强了传统细胞毒性药物的抗肿瘤疗效。这项工作表明多胺生物合成是MYCN肿瘤发生的仲裁者，并显示了多胺消耗策略在神经母细胞瘤中的初步疗效，该策略可能对这种以及其他MYC驱动的胚胎肿瘤有用。
