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.

该提案的目标是为使用血癌药物提供体内概念验证