Resistance mechanisms to autophagy-modulating therapies

自噬调节疗法的耐药机制

基本信息

批准号：
10565868
负责人：
RAVI K AMARAVADI
金额：
$ 64.12万
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/10565868
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 Macrophage 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 comparison control 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 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.

项目概要尽管靶向治疗和免疫检查点抑制剂对患者的生存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。免疫治疗的疗效。测试自噬抑制剂组合的临床试验显示令人鼓舞的初步结果与标准护理方法相比，结果具有更高的响应率。新型自噬抑制剂正在进入临床试验。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耐药性。有一个关键的未满足的需求需要理解自噬调节治疗的抵抗机制。使用黑色素瘤作为模型，我们有发现自噬调节疗法可诱导广泛的脂筏诱导。这尤其是溶酶体自噬抑制作用明显，可诱导关键蛋白（LDLR、SR-B1、和 UGCG）在胆固醇和鞘脂补救途径（CSSP）中。这些酶中至少一种， UGCG，可以用 FDA 批准的治疗药物 Eliglustat 来靶向，初步结果表明联合治疗自噬抑制和 UGCG 抑制在体内产生协同抗肿瘤活性。该提案将测试假设 CSSP 表达增加以及随后的脂筏形成自噬调节疗法可促进细胞存活，并且可能是一个关键的药物脆弱性，可以旨在改善癌症的治疗结果。为了检验这个假设，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。我们还聘请了黑色素瘤专家 Meenhard Herlyn 博士，他开发了人源化小鼠模型并患者来源的异种移植物库，以及与他密切合作的生物统计学家 Phyllis Ginotty 博士这个团队多年来。在目标 1 中，我们将定义自噬调节调节自噬的机制。胆固醇和鞘脂清除途径（CSSP）。我们将确定化学或遗传的影响在去脂和精确重构的培养基中对肿瘤细胞的关键 CSSP 基因进行操作抑制生存。在目标 2 中，我们将确定 UGCG 作为黑色素瘤治疗耐药性驱动因素的作用体内模型中的组合。我们将利用一组源自患者的异种移植（PDX）模型 BRAF 突变和 NRAS 突变黑色素瘤患者确定靶向 UGCG 是否会导致血脂降低筏组装，克服了对临床相关疗法的耐药性。影响：这些研究将决定癌症治疗的两种关键耐药机制——自噬和脂质代谢改变——如何交叉。我们的结果应该揭示黑色素瘤和其他癌症的新治疗漏洞，并应该确定包含 CSSP 抑制剂的新治疗组合将在未来的临床试验中进行测试，这可能显着改善癌症患者的治疗结果。