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Resistance mechanisms to autophagy-modulating therapies

自噬调节疗法的耐药机制

基本信息

批准号：
10345115
负责人：
RAVI K AMARAVADI
金额：
$ 66.99万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10345115
关键词：
Address Advanced Malignant Neoplasm Antigen Presentation Autophagocytosis BRAF gene Biotechnology CD8-Positive T-Lymphocytes Cancer Model Cancer Patient Cell Death Cell Survival Cell membrane Cell-Mediated Cytolysis Cells Ceramide glucosyltransferase Chemicals Cholesterol Clinic Clinical Clinical Data Clinical Trials Collaborations Combined Modality Therapy Development Enzymes Exhibits FDA approved Future Generations Genes Glean Hydroxychloroquine Immune Immune checkpoint inhibitor Immunotherapy Institution Knowledge Lipids Low Density Lipoprotein Receptor Lysosomes MAP Kinase Gene MEK inhibition MEKs Malignant Neoplasms Malignant neoplasm of pancreas Measures Melanoma Cell Membrane Microdomains Metabolic Modeling Oncologist Pathway interactions Patient-Focused Outcomes Patients Phenotype Pre-Clinical Model Proteins Randomized Regimen Resistance Resistance development Role SR-B proteins Sampling Source Sphingolipids Systems Biology T-Cell Activation Testing Therapeutic Toxic effect Tumor Immunity Tumor-associated macrophages Work anti-PD1 antibodies antitumor agent cancer clinical trial cancer therapy chemotherapy clinically relevant enzyme pathway experimental study extracellular first-in-human genetic manipulation humanized mouse improved improved outcome in vivo in vivo Model inhibition of autophagy inhibitor lipid metabolism lipidome macrophage melanoma mouse model mutant neoplastic cell new combination therapies novel novel therapeutic intervention novel therapeutics overexpression palmitoyl-protein hydrolase patient derived xenograft model phase I trial phase II trial pre-clinical preclinical study reconstitution recruit resistance mechanism response standard of care targeted agent targeted treatment therapy outcome tumor tumor growth

项目摘要

Project Summary Although targeted therapy and immune checkpoint inhibitors have made a major impact on survival for some patients with advanced cancer, the majority of patients do not respond to standard of care treatments. Abundant evidence indicates autophagy is induced by chemotherapy and targeted therapy, and also limits the efficacy of immunotherapy. Clinical trials testing autophagy inhibitor combinations show encouraging preliminary results with increased response rates when compared to standard of care approaches. New autophagy inhibitors are entering clinical trials. Preclinical studies and the available clinical data indicate that tumors can overcome autophagy modulating therapies producing resistance. There is a critical unmet need to understand mechanisms of resistance to autophagy-modulating therapy. Using melanoma as a model we have discovered that extensive lipid raft induction is induced by autophagy modulating therapy. This is especially pronounced with lysosomal autophagy inhibition, which induces the expression of key proteins (LDLR, SR-B1, and UGCG) in the cholesterol and sphingolipid salvage pathways (CSSP). At least one of these enzymes, UGCG, can be targeted with an FDA approved therapy eliglustat and preliminary results indicate combined autophagy inhibition and UGCG inhibition produces synergistic antitumor activity in vivo. This proposal will test the hypothesis that the increased expression of CSSP and subsequent lipid raft formation induced by autophagy-modulating therapy promotes cell survival, and may be a key druggable vulnerability that can be targeted to improve therapeutic outcomes in cancer. To test this hypothesis, we will leverage the longstanding collaboration between Dr. Amaravadi (oncologist, autophagy expert) and Dr. Speicher (systems biology expert). We also recruited Dr. Meenhard Herlyn, a melanoma expert who has developed a humanized mouse model and bank of patient-derived xenografts, as well as Dr. Phyllis Ginotty, a biostatistician who has worked closely with this team for years. In Aim 1 we will define the mechanism by which autophagy modulation regulates the cholesterol and sphingolipid scavenging pathways (CSSP). We will determine the effects of chemical or genetic manipulation inhibition of key CSSP genes in lipid-depleted and precisely reconstituted media on tumor cell survival. In Aim 2 we will determine the role of UGCG as a driver of resistance across melanoma therapy combinations in in vivo models. We will utilize a panel of patient-derived xenograft (PDX) models generated from BRAF mutant and NRAS mutant melanoma patients to determine if targeting UGCG results in decreased lipid raft assembly, that overcomes resistance to clinically relevant therapies. Impact: These studies will determine how two key resistance mechanisms to cancer therapies, autophagy and altered lipid metabolism, intersect. Our results should uncover new therapeutic vulnerabilities in melanoma as well as other cancers and should identify new therapeutic combinations incorporating CSSP inhibitors to be tested in future clinical trials, which could significantly improve outcomes for cancer patients.

项目摘要尽管靶向治疗和免疫检查点抑制剂对患者的生存率产生了重大影响，对于一些晚期癌症患者，大多数患者对标准护理治疗没有反应。大量证据表明，自噬是由化疗和靶向治疗诱导的，也限制了自噬的发生。免疫治疗的功效。测试自噬抑制剂组合的临床试验显示了令人鼓舞的初步结果结果与标准护理方法相比，应答率增加。新的自噬抑制剂正在进入临床试验阶段临床前研究和现有的临床数据表明，肿瘤可以克服自噬调节疗法产生抗性。有一个关键的未满足的需求需要了解对自噬调节疗法的抗性机制。以黑素瘤为模型，发现广泛的脂筏诱导是由自噬调节疗法诱导的。这是特别溶酶体自噬抑制明显，其诱导关键蛋白（LDLR，SR-B1，和UGCG）在胆固醇和鞘脂补救途径（CSSP）中的作用。这些酶中的至少一种， UGCG可以用FDA批准的治疗eliglustat靶向治疗，初步结果表明，自噬抑制和UGCG抑制在体内产生协同抗肿瘤活性。该提案将测试假设CSSP的表达增加和随后的脂筏形成诱导自噬调节疗法促进细胞存活，可能是一个关键的药物脆弱性，旨在改善癌症的治疗效果。为了验证这一假设，我们将利用长期存在的 Amaravadi博士（肿瘤学家，自噬专家）和Speicher博士（系统生物学专家）之间的合作。我们还招募了Meenhard Herlyn博士，他是一位黑色素瘤专家，他开发了一种人源化小鼠模型，患者来源的异种移植物库，以及Phyllis Ginotty博士，一位生物统计学家，这个团队多年来。在目标1中，我们将定义自噬调节调节细胞凋亡的机制。胆固醇和鞘脂清除途径（CSSP）。我们将确定化学或基因的影响在脂质耗尽和精确重构的培养基中对肿瘤细胞的关键CSSP基因的操纵抑制生存在目标2中，我们将确定UGCG作为黑色素瘤治疗耐药驱动因素的作用在体内模型中的组合。我们将利用一组患者来源的异种移植物（PDX）模型， BRAF突变型和NRAS突变型黑色素瘤患者，以确定靶向UGCG是否导致血脂降低筏组装，克服了临床相关治疗的阻力。影响：这些研究将决定癌症治疗的两个关键抗性机制，自噬和脂质代谢改变，如何交叉。我们结果应该揭示黑色素瘤和其他癌症的新的治疗弱点，新的治疗组合，包括CSSP抑制剂，将在未来的临床试验中进行测试，显著改善癌症患者的预后。