Cell-targeted glutamine antagonists as a novel therapy for lymphoma

细胞靶向谷氨酰胺拮抗剂作为淋巴瘤的新疗法

基本信息

批准号：
10197023
负责人：
Barbara Stauch Slusher
金额：
$ 49.62万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-02 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197023
关键词：
Acute Lymphocytic Leukemia Address Adverse event American Cancer Society Animal Model Antiviral Agents Blood Blood Cells Burkitt Lymphoma Cells Cessation of life Chemistry Clinical Clinical Research Clinical Trials Cytotoxic Chemotherapy Data Development Diagnosis Diarrhea Diffuse Large-Cell Lymphoma Disease Disease remission Dose Dose-Limiting Drug Kinetics Drug or chemical Tissue Distribution Energy Metabolism Ensure Enzymes Event Exhibits Family suidae Generations Glucose Glutamine Goals Grant Growth Hematologic Neoplasms Hodgkin Disease Human Image Immunotherapy Incubated Intestines Lead Liver Microsomes Luciferases Lymphocyte Lymphoid Lymphoid Cell Lymphoma Lymphoma cell Malignant Neoplasms Masks Metabolic Metabolism Methods Microsomes Modeling Molecular Monitor Mus Nausea and Vomiting Norleucine Nucleic Acids Outcome Parents Pathology Pathway interactions Patients Peripheral Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Plasma Prodrugs Proteins Reaction Regimen Regulatory T-Lymphocyte Resistance Site Symptoms Tenofovir Testing Therapeutic Therapeutic Index Tissues Toxic effect Translations United States Work Xenograft procedure alpha ketoglutarate amino group anti-PD1 therapy base c-myc Proto-Oncogenes cancer cell carboxylate clinical candidate design drug discovery efficacy testing gastrointestinal gastrointestinal system head-to-head comparison improved in vivo inhibitor/antagonist liquid chromatography mass spectrometry lymphoid neoplasm mouse model neoplastic cell novel novel therapeutics older patient potential biomarker scale up screening side effect success therapeutic target transcription factor tumor tumor metabolism tumor microenvironment tumor-immune system interactions

项目摘要

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.

在美国，每 3 分钟大约就有 1 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 人患有该疾病，尽管有许多已获批准的治疗方法，但美国癌症中心仍处于缓解状态。协会估计仅今年就有近 58,000 人死亡，而一些血液病患者则死亡。使用细胞毒性化疗可以治愈年轻患者的恶性肿瘤（例如霍奇金病、急性淋巴细胞白血病、弥漫性大细胞淋巴瘤、伯基特淋巴瘤），更严重的副作用老年患者的结果不太乐观，因此，不仅需要另一种方法。一般而言，但对于老年患者尤其理想，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，并成为淋巴瘤是这种癌症的一个明显例子。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合成核酸、蛋白质以及生成用于能量代谢的α-酮戊二酸。 DON 在淋巴瘤动物模型和探索性临床研究中均显示出强大的功效，但其由于明显的剂量限制毒性，其中许多是胃肠道（GI）毒性，开发被停止相关的，因为胃肠道系统高度依赖于谷氨酰胺的利用，我们探索了一种新的细胞- DON 的定向前药可以选择性地将药物递送至淋巴细胞，从而允许显着减少剂量，大大减轻不良事件，这种方法的可行性是。吉利德的淋巴细胞靶向抗病毒药物替诺福韦前药最近取得的成功支持了这一点，称为替诺福韦艾拉酚胺 (TAF)，在 3 期临床试验中以 30 倍的剂量提供了类似的功效通过利用类似的概念并采取独特的分子设计策略，我们已经确定了一种最初的主要 DON 前药 JHU-083，它优先向体内输送 30 倍以上的 DON 外周血单核细胞 (PBMC) 与人血浆的比较，并表现出与 DON 相似的功效组织研究结果显示，小鼠淋巴瘤模型的毒性显着降低。猪体内的分布/耐受性研究证实了前药的 PBMC 靶向性。与等摩尔 DON 相比，DON 前药显示 DON 向 PBMC 的递送增强，并且减少对胃肠道组织的输送，从而减少胃肠道病理和临床症状。 JHU-083 有希望，但它并不适合翻译，因为它表现出高清除率，因此，这是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，从而使其在这项资助中，两名具有互补专业知识的 PI 将能够维持 DON 的淋巴细胞输送。设计具有优化药代动力学参数的新型 DON 前药并表征其功效/ 在完成这些研究后，我们将开发出淋巴瘤小鼠模型的毒性特征。我们的研究将为谷氨酰胺代谢的快速发展奠定基础。将此类化合物引入临床试验。