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，每3分钟大约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。尽管有许多批准的疗法，但美国癌症社会估计，仅今年，今年将有近58,000人死亡。而许多血液学使用细胞毒性化学疗法在年轻患者（例如霍奇金斯疾病，急性淋巴细胞性白血病，弥漫性大细胞淋巴瘤，伯基特的淋巴瘤），在老年患者的乐观结局较少。不仅需要一种替代方法一般，但在老年患者中尤其可取。我们和其他人表明转录因子原始癌基因C-MYC驱动某些癌症改变其能量代谢要求，并成为 “谷氨酰胺上瘾”的生长和生存。淋巴瘤是这种癌症的明显例子。这谷氨酰胺拮抗剂6-diazo-5-oxo-l-甲氨酸（DON）广泛阻断谷氨酰胺利用反应关键为了合成核酸，蛋白质和α-酮戊二酸α-用于能量代谢。 DON在淋巴瘤动物模型和探索性临床研究中都表现出强大的效率，但由于明显的剂量限制战术而停止了发展，其中许多是胃肠道（GI） - 相关，因为GI系统高度依赖于谷氨酰胺的利用率。我们假设一个新颖的细胞 - 定向的DON前药可以选择地将药物递送到淋巴样细胞大量剂量减少，极大地减轻了不良事件。这种方法的可行性是在吉利德（Gilead）淋巴细胞靶向抗病毒剂Tenofovir的前药的最新成功的支持下，称为Tenofovir Alafenamide（TAF），在pH 3临床试验中，剂量相似，剂量相似降低和毒性较小。通过利用类似的概念但采用独特的分子设计策略，我们已经确定了最初的铅Don Prodrug，Jhu-083，优先将30倍的DON提供给外周血单核细胞（PBMC）与人血浆，表现出与DON相似的效率在鼠淋巴瘤模型中的毒性大大降低。来自组织的发现猪中的分布/出租性研究证实了前药的PBMC靶向。在正面比较与等摩尔don，DON Prodrug显示了增强的DON向PBMC递送，并且减少了向胃肠道组织的递送，导致胃肠道病理学较少，临床症状较少。虽然有希望的是，JHU-083并不理想翻译，因为它具有高间隙。那，我们的主要药物发现重点将是创建新颖的Don Protrugs，这些原始原始在等离子体和微粒体中保持完整，以便它们 DON的淋巴细胞递送可以维持。在这笔赠款中，两个具有免费专业知识的PI将设计小说的Don Prodrugs具有优化的药代动力学参数，并表征其有效性/ 淋巴瘤小鼠模型中的毒性谱。这些研究完成时，我们将开发谷氨酰胺代谢的新颖，健壮和安全的抑制剂。我们的研究将为快速奠定基础工作将这种化合物引入临床试验中。