Cell-targeted glutamine antagonists as a novel therapy for lymphoma

在美国，大约每3分钟就有一个人被诊断出患有血细胞癌， 2016年估计有171，550例新病例。预计有1,237,824人患有这种疾病， 或正在缓解。尽管事实上有一些批准的疗法，美国癌症 社会估计，仅今年就有近58,000人死亡。虽然一些血液学 在年轻患者中使用细胞毒性化疗治愈恶性肿瘤（例如霍奇金斯病，急性 淋巴细胞白血病、弥漫性大细胞淋巴瘤、伯基特淋巴瘤）， 年龄较大的患者导致不太乐观的结果。因此，不仅需要一种替代方法， 这是普遍的，但特别适用于老年患者。我们和其他人已经证明转录因子 原癌基因c-Myc驱动某些癌症改变其能量代谢需求， “谷氨酰胺成瘾”对他们的生长和生存。淋巴瘤是这种癌症的一个明显的例子。的 谷氨酰胺拮抗剂6-重氮-5-氧代-L-正亮氨酸（DON）广泛阻断谷氨酰胺利用关键反应 用于核酸、蛋白质的合成和用于能量代谢的α-酮戊二酸的产生。 DON在淋巴瘤动物模型和探索性临床研究中都显示出强大的功效，但其 由于明显的剂量限制性毒性，其中许多是胃肠道（GI）毒性， 相关，因为GI系统高度依赖于谷氨酰胺的利用。我们假设一种新的细胞- DON的定向前药可以选择性地将药物递送至淋巴细胞， 显著减少剂量，大大减轻不良事件。这种方法的可行性是 最近吉利德的抗病毒药物替诺福韦的淋巴细胞靶向前体药物的成功支持了这一点， 这种药物被称为替诺福韦艾拉酚胺（TAF），在3期临床试验中， 还原性和低毒性。通过利用类似的概念，但采取独特的分子设计策略，我们 已经鉴定了最初的先导DON前药JHU-083，其优先递送30倍以上的DON， 外周血单核细胞（PBMC）与人血浆，并表现出类似的疗效DON 在鼠淋巴瘤模型中毒性显著降低。组织检查结果 在猪中的分布/耐受性研究证实了前药的PBMC靶向。面对面 与等摩尔DON相比，DON前药显示出增强的DON向PBMC的递送， 减少递送至GI组织，导致更少的GI病理和更少的临床症状。虽然 虽然JHU-083很有前途，但由于它具有高清除率，因此不适合翻译。因此，我们的主要药物发现 重点将是创造在血浆和微粒体中保持完整的新型DON前药， DON的淋巴细胞递送可以持续。在这项拨款中，两名具有互补专业知识的PI将 设计具有优化的药代动力学参数的新型DON前药并表征其功效/ 淋巴瘤小鼠模型中的毒性特征。在完成这些研究后，我们将制定一个 一种新型、稳定、安全的谷氨酰胺代谢抑制剂。我们的研究将为快速发展奠定基础 将这些化合物引入临床试验。

Every 3 minutes approximately one person in the United States is diagnosed with a blood cell cancer with an estimated 171,550 new cases in 2016. A projected 1,237,824 people are either living with the disease, or are in remission. In spite of the fact there are a number of approved therapies, the American Cancer Society estimates there will be almost 58,000 deaths this year alone. While a number of hematologic malignancies are cured using cytotoxic chemotherapy in younger patients (e.g. Hodgkins Disease, Acute Lymphocytic Leukemia, Diffuse Large Cell Lymphoma, Burkitt's lymphoma), the more intense side effects in older patients results in less sanguine outcomes. Thus an alternative approach is not only needed in general, but particularly desirable in older patients. We and others have shown that the transcription factor proto-oncogene c-Myc drives certain cancers to change their energy metabolic requirements, and become “glutamine addicted” for their growth and survival. Lymphoma is a clear example of such a cancer. The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) broadly blocks glutamine utilizing reactions critical for the synthesis of nucleic acids, proteins and the generation of alpha-ketoglutarate for energy metabolism. DON has shown robust efficacy in both lymphoma animal models and exploratory clinical studies, but its development was halted due to marked dose-limiting toxicities, many of which were gastrointestinal (GI)- related, as the GI system is highly dependent on glutamine utilization. We hypothesized that a novel cell- directed prodrug of DON which could deliver the drug selectively to the lymphoid cells would permit significant dose reduction, greatly alleviating the adverse events. The feasibility of this approach is supported by the recent success of Gilead's lymphoid cell-targeted prodrug of the antiviral agent tenofovir, called tenofovir alafenamide (TAF), which in Ph 3 clinical trials provided similar efficacy with a 30-fold dose reduction and less toxicity. By exploiting a similar concept yet taking a unique molecular design strategy, we have identified an initial lead DON prodrug, JHU-083, which preferentially delivers 30-fold more DON to peripheral blood mononuclear cells (PBMCs) versus human plasma, and exhibits similar efficacy to DON with substantially reduced toxicity in murine lymphoma models. Findings from a tissue distribution/tolerability study in swine confirms the PBMC targeting of the prodrug. In head-to-head comparison versus equimolar DON, the DON prodrug showed enhanced DON delivery to PBMCs and reduced delivery to GI tissues resulting in less GI pathology and fewer clinical symptoms. Although promising, JHU-083 is not ideal for translation as it exhibits high clearance. Thus, our main drug discovery focus will be to create novel DON prodrugs which remain intact in plasma and microsomes, such that their lymphocyte delivery of DON can be sustained. In this grant, two PIs with complimentary expertise will design novel DON prodrugs with optimized pharmacokinetic parameters and characterize their efficacy/ toxicity profiles in lymphoma mouse models. At the completion of these studies we will have developed a novel, robust and safe inhibitor of glutamine metabolism. Our studies will lay the ground work for the rapid introduction of such compounds into clinical trials.