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

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

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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.

项目摘要尽管有针对性的治疗和免疫检查点抑制剂对生存产生了重大影响一些患有晚期癌症的患者，大多数患者对护理治疗的标准不反应。大量证据表明自噬是由化学疗法和靶向治疗引起的，也限制了自噬。免疫疗法的功效。临床试验测试自噬抑制剂组合表明了令人鼓舞的初步与护理标准方法相比，响应率提高的结果。新的自噬抑制剂正在进入临床试验。临床前研究和可用的临床数据表明肿瘤可以克服自噬调节疗法产生抗药性。有关键的未满足需要了解的对自噬调节疗法的抗性机制。使用黑色素瘤作为模型，我们有发现自噬调节疗法诱导广泛的脂质筏诱导。尤其是用溶酶体自噬抑制（诱导关键蛋白的表达）发音（LDLR，SR-B1，和UGCG）中的胆固醇和鞘脂拯救途径（CSSP）。这些酶中的至少一种， UGCG，可以通过FDA认可的疗法来瞄准，初步结果表明合并自噬抑制和UGCG抑制作用在体内产生协同抗肿瘤活性。该建议将测试假设CSSP的表达增加以及随后的脂质筏形成由自噬调节疗法可促进细胞存活，并且可能是可药物的关键脆弱性针对改善癌症治疗结果的目标。为了检验这一假设，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。我们还招募了黑色素瘤专家Meenhard Herlyn博士，他开发了人源化的老鼠模型，与患者衍生的异种移植物以及生物统计学家菲利斯·吉诺蒂（Phyllis Ginotty）博士这个团队多年。在AIM 1中，我们将定义自噬调节调节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脂质细胞中抑制关键CSSP基因的操纵抑制在肿瘤细胞上生存。在AIM 2中，我们将确定UGCG作为黑色素瘤疗法抗药性的作用体内模型中的组合。我们将利用一组由患者衍生的异种移植（PDX）模型 BRAF突变体和NRAS突变体黑色素瘤患者以确定靶向UGCG是否导致脂质降低筏组件，克服了对临床相关疗法的抵抗力。影响：这些研究将决定如何相交的癌症疗法，自噬和改变的脂质代谢的两种关键抗性机制。我们的结果应发现黑色素瘤和其他癌症的新治疗脆弱性在以后的临床试验中，掺入将测试的CSSP抑制剂的新的治疗组合，可以测试癌症患者的预后可显着改善。