Expanding the efficacy of asparaginase to solid tumors

将天冬酰胺酶的功效扩展到实体瘤

• 批准号: 10582953
• 负责人: ARNON LAVIE
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582953
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adult; Amino Acid Transporter; Amino Acids; Antineoplastic Agents; Asparagine; Aspartate-Ammonia Ligase; Biological; Biological Markers; Biopsy; Blood; Cancer Patient; Cancer cell line; Cell Line; Cells; Childhood; Childhood Acute Lymphocytic Leukemia; Clinical; Clinical Trials; Data; Development; Drug Side Effects; Drug resistance; Engineering; Enzymes; FDA approved; Funding; Genetic; Genomics; Glutaminase; Goals; Hematopoietic Neoplasms; Human; Human Engineering; Hypermethylation; Immune response; In Vitro; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Messenger RNA; Methylation; Minority; Minority Groups; Mus; Nature; Organoids; Patient Selection; Patients; Pegaspargase; Phagocytosis; Pharmaceutical Preparations; Predisposition; Prevalence; Primary carcinoma of the liver cells; Reagent; Reporting; Resected; Resistance; Safety; Sampling; Side; Solid Neoplasm; Starvation; Stomach; Testing; Therapeutic; Toxic effect; Translating; Tumor Volume; Up-Regulation; Validation; Veterans; Work; acute lymphoblastic leukemia cell; asparaginase; biomarker validation; blood treatment; cancer cell; cancer type; clinically relevant; comparison control; design; efficacy evaluation; genomic signature; hepatocellular carcinoma cell line; immunogenic; improved; improved outcome; in vivo; malignant stomach neoplasm; military veteran; neoplastic cell; novel; novel strategies; patient derived xenograft model; patient population; patient stratification; personalized medicine; pre-clinical; predicting response; predictive signature; predictive test; prevent; promoter; response; response biomarker; side effect; standard of care; success; theories; tool; treatment comparison; tumor; validation studies

The goal of this proposal is to provide in vivo proof-of-concept for the use of the blood cancer drug asparaginase (ASNase) in hepatocellular carcinoma (HCC) patients who possess the biomarkers for response to this novel biologic. ASNases have a unique mode of action wherein the drug depletes the amino acid asparagine from the blood, and, as a result, cells that rely on blood asparagine are starved and ultimately killed. The current FDA-approved ASNases are of bacterial origin, which makes them immunogenic, and their toxicity-causing glutaminase (GLNase) side activity causes severe drug side effects, which are exacerbated in adults. Therefore, despite the immense potential of ASNases for the treatment of several cancer types, these drugs are predominately confined to the treatment of pediatric acute lymphoblastic leukemia (ALL). To make ASNase therapy an option for adult patients with cancers that depend on blood asparagine, we engineered a human-like ASNase that mitigates the immune response and is highly specific to eliminate the GLNase-related toxicity. Notably, toxicity studies comparing our engineered human-like ASNase to the current standard-of-care bacterial ASNase (Oncaspar) demonstrated the significantly improved safety of our ASNase. Importantly, the improved safety comes with equivalent efficacy for ALL. Together, these developments make it possible to expand ASNase therapy to solid tumors in adult cancer patients. Response to ASNase is dependent on no/low expression of the enzyme that synthesizes asparagine de novo, called asparagine synthetase (ASNS). However, a durable response requires the inability of the cancer cell to upregulate ASNS expression in response to asparagine depletion. The ability to upregulate ASNS expression is determined by the methylation state of the ASNS promoter, where hypermethylation prevents expression and hypomethylation allows for expression. Recent analysis of cancer cell lines and patient samples reveal that many HCC patients possess either the full ASNase-response signature (low ASNS levels, hypermethylated promoter) or partial ASNase- response signature (low ASNS levels, hypomethylated promoter). Tumor cells with the full signature are predicted to strongly respond to ASNase alone, and those with the partial signature are predicted to have a less durable response. In preliminary work, we verified the predictive power of the full and partial ASNase response signatures on several HCC cell lines. To increase the clinical relevance of this observation, in Aim 1 we will collect HCC tumor samples from Veterans (treated at JBVAMC) and from a predominantly minority population (treated at UIC) and determine the predisposition of these patients to possess the ASNase- sensitivity biomarkers. These patient samples will also be used to generate HCC primary cell line, organoid, and PDX models. In Aim 2, using both in vitro and in vivo studies, we will determine the factor(s) that make HCC cell lines sensitive or resistant to ASNase therapy. Aim 3 will expand the in vivo studies to the patient- derived cell lines, organoids and PDXs generated in Aim 1, and evaluate our ability to predict which patients will respond to ASNase therapy. Success in these studies will supply the proof-of-concept for using our new, safer ASNase in HCC. Moreover, by utilizing mechanistically based biomarkers we would be able to identify those patients that would respond to ASNase. Success will also provide the impetus for testing this novel approach in other cancers, using the biomarkers validated by these studies for patient selection.

该提案的目标是为血癌药物的使用提供体内概念验证 具有反应生物标志物的肝细胞癌 (HCC) 患者中的天冬酰胺酶 (ASNase) 对于这种新颖的生物制剂。 ASNases 具有独特的作用模式，其中药物消耗氨基酸 血液中的天冬酰胺，结果，依赖血液天冬酰胺的细胞挨饿，最终 被杀了。目前 FDA 批准的 ASNase 是细菌来源的，这使得它们具有免疫原性，并且它们的 引起毒性的谷氨酰胺酶（GLNase）副作用会导致严重的药物副作用，这种副作用在以下情况下会加剧： 成年人。因此，尽管 ASNase 在治疗多种癌症方面具有巨大潜力，但这些 药物主要限于治疗儿童急性淋巴细胞白血病（ALL）。使 ASNase 疗法是依赖血液天冬酰胺的成年癌症患者的一种选择，我们设计了一种 类人 ASNase，可减轻免疫反应，并且高度特异性地消除 GLNase 相关的 毒性。值得注意的是，毒性研究将我们的工程类人 ASNase 与当前的护理标准进行了比较 细菌 ASNase (Oncaspar) 证明我们的 ASNase 的安全性显着提高。重要的是， 安全性的提高与对 ALL 具有同等功效。总之，这些发展使我们有可能 将 ASNase 疗法扩展到成年癌症患者的实体瘤。对 ASNase 的反应取决于无/低 表达从头合成天冬酰胺的酶，称为天冬酰胺合成酶 (ASNS)。 然而，持久的反应需要癌细胞无法上调 ASNS 表达 对天冬酰胺消耗的反应。上调 ASNS 表达的能力由甲基化决定 ASNS 启动子的状态，其中高甲基化阻止表达，低甲基化允许 表达。最近对癌细胞系和患者样本的分析表明，许多 HCC 患者具有 完整的 ASNase 响应特征（低 ASNS 水平、高甲基化启动子）或部分 ASNase 响应特征 响应特征（低 ASNS 水平、低甲基化启动子）。具有完整签名的肿瘤细胞是 预计对单独的 ASNase 会有强烈反应，而那些具有部分特征的人预计会有 反应不太持久。在前期工作中，我们验证了完整和部分 ASNase 的预测能力 几种 HCC 细胞系的反应特征。为了提高这一观察结果的临床相关性，目标 1 我们将从退伍军人（在 JBVAMC 接受治疗）和主要少数群体中收集 HCC 肿瘤样本 人群（在 UIC 接受治疗）并确定这些患者拥有 ASNase-的倾向 敏感性生物标志物。这些患者样本还将用于生成 HCC 原代细胞系、类器官、 和 PDX 模型。在目标 2 中，我们将利用体外和体内研究来确定导致 HCC 细胞系对 ASNase 治疗敏感或耐药。目标 3 将把体内研究扩展到患者—— 目标 1 中生成的衍生细胞系、类器官和 PDX，并评估我们预测哪些患者的能力 对 ASNase 治疗有反应。这些研究的成功将为使用我们新的、 在 HCC 中更安全的 ASNase。此外，通过利用基于机械的生物标志物，我们将能够识别 那些对 ASNase 有反应的患者。成功也将为测试这部小说提供动力 其他癌症的方法，使用这些研究验证的生物标志物来选择患者。