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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：
10408137
负责人：
Barbara Stauch Slusher
金额：
$ 48.62万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408137
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 antagonist 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 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，大约每3分钟就有一人被诊断出患有血细胞癌据估计，2016年有171,550例新病例。预计有1,237,824人要么患有这种疾病，或者处于缓解期。尽管有许多已获批准的治疗方法，但美国癌症该协会估计，仅今年一年就会有近5.8万人死亡。而一些血液病患者在年轻患者中使用细胞毒性化疗治愈恶性肿瘤(例如霍奇金氏病、急性淋巴细胞性白血病、弥漫性大细胞淋巴瘤、Burkitt淋巴瘤)，副作用越严重年龄较大的患者结果不那么乐观。因此，不仅需要另一种方法一般，但尤其适用于老年患者。我们和其他人已经证明了转录因子原癌基因c-Myc驱动某些癌症改变其能量代谢需求，并成为 “谷氨酰胺成瘾”为他们的成长和生存。淋巴瘤就是这种癌症的一个明显的例子。这个谷氨酰胺拮抗剂6-重氮-5-氧代-L去亮氨酸(DON)广泛阻断谷氨酰胺利用关键反应用于合成核酸、蛋白质和生成能量代谢所需的α-酮戊二酸。 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疗效，但其由于显著的剂量限制毒性，开发被停止，其中许多是胃肠道(GI)- 相关，因为胃肠道系统高度依赖谷氨酰胺的利用。我们假设一种新的细胞- 可以选择性地将药物输送到淋巴细胞的定向前药DON将允许剂量显著减少，大大缓解了不良事件。这种方法的可行性是在吉列德的淋巴细胞靶向前药抗病毒药物替诺福韦最近取得成功的支持下，名为替诺福韦丙氨酰胺(TAF)，在Ph3临床试验中提供了30倍剂量的类似疗效减少，毒性更小。通过利用类似的概念，但采取了独特的分子设计策略，我们已经确定了一种最初的先导药物JHU-083，它优先提供30倍于外周血单个核细胞(PBMCs)与人血浆相比，显示出与DON相似的疗效在小鼠淋巴瘤模型中毒性显著降低。从纸巾上发现的东西在猪体内的分布/耐受性研究证实了前药的PBMC靶向。面对面地与等摩尔DON相比，DON前药显示DON对PBMCs和减少对胃肠道组织的投放，导致胃肠道病理和临床症状减少。虽然前景看好，JHU-083不是理想的翻译，因为它表现出高清晰度。因此，我们的主要药物发现重点将是创造新的DON前药，这种药物在血浆和微粒体中保持完好，这样他们的 DON的淋巴细胞传递是可以持续的。在这笔赠款中，两名具有互补专业知识的私人助理将优化药代动力学参数设计新型DON前药并表征其药效淋巴瘤小鼠模型的毒性分析。在这些研究完成后，我们将制定一项新型、强效、安全的谷氨酰胺代谢抑制剂。我们的研究将为RAPH奠定基础将此类化合物引入临床试验。