Mechanisms of cell death in cutaneous melanoma

皮肤黑色素瘤细胞死亡的机制

基本信息

批准号：
10612054
负责人：
Emad S Alnemri
金额：
$ 46.83万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612054
关键词：
Address Adjuvant Affect Antibodies Apoptosis Apoptotic BRAF gene Bioinformatics Biological Assay Biology CASP3 gene CD8-Positive T-Lymphocytes Caspase Cell Death Cell Therapy Cells Clinical Clinical Trials Collaborations Communication Complement Cutaneous Melanoma DNA Data Dendritic Cells Disease Resistance Drug Tolerance Eating Excision Exclusion Exhibits FDA approved Goals Growth High Mobility Group Proteins Immune Immune checkpoint inhibitor Immune response Immune system Immunotherapy Incidence Knock-out Knockout Mice Leucocytic infiltrate Link MEKs Malignant Neoplasms Mediating Melanoma Cell Modeling Molecular Nature Nivolumab Pathway interactions Patients Pattern Pharmaceutical Preparations Phosphorylation Population Process Publishing Quality of life Regimen Regulation Residual Neoplasm Resistance Role Signal Pathway Signal Transduction Stress T-Lymphocyte TP53 gene Testing Therapeutic Toxic effect Tumor-infiltrating immune cells Work adaptive immune response anti-CTLA4 anti-PD-1 anti-tumor immune response cancer cell cancer therapy checkpoint inhibition checkpoint therapy chemotherapy cytokine design immune cell infiltrate immune checkpoint immunogenic immunogenic cell death immunogenicity improved in vivo in vivo Model inducible gene expression inhibitor insight ipilimumab melanoma multidisciplinary mutant neoantigens neoplastic cell novel novel therapeutic intervention pembrolizumab pharmacologic pre-clinical prevent rational design resistance mechanism response single cell analysis small molecule standard of care synergism targeted treatment treatment response treatment strategy tumor tumor growth tumor-immune system interactions

项目摘要

PROJECT SUMMARY The incidence of cutaneous melanoma is rising. While small molecule targeted inhibitors and immune checkpoint antibodies have increased long-term survival in advanced-stage cutaneous melanoma, many patients still do not benefit and regimens are associated with high toxicity. We are studying the determinants of treatment response and mechanisms of resistance in melanoma. From our studies, we aim to generate pre- clinical data for new combinations that delay/prevent the onset of acquired resistance while minimizing patient toxicities in order to improve patient survival and quality of life. Multiple clinical trials have emanated from our work (NCT03580382, NCT02012231, NCT02683395). Tumor immunogenicity, defined as the ability of the tumor itself to trigger an anti-tumor adaptive immune response, is one of the most important determinants of successful anti-cancer therapy. The immunogenicity of a tumor depends on its antigenicity, conferred by neo- antigens, and also by adjuvant effects triggered by damage-associated molecular patterns (DAMPs) released from stressed or dying tumor cells during a process called immunogenic cell death (ICD). We recently discovered a signaling pathway that allows efficient release of DAMPs from dying cells by switching apoptosis into a potentially immunogenic form of cell death called pyroptosis. Mechanistically, activation of caspase-3 during apoptosis leads to cleavage of gasdermin E (GSDME), generating a pore-forming GSDME-N fragment. GSDME-N pores allow release of intracellular DAMPs such as HMGB1, DNA, and ATP. The ability of this novel pathway to switch apoptosis into pyroptosis suggests that GSDME-induced pyroptosis is likely a key effector of cancer cell immunogenicity and may determine their successful response to various anti-cancer therapies. Supporting this hypothesis, our preliminary data revealed that efficient BRAFi + MEKi-induced anti- tumor immune responses in melanoma cells are dependent, at least in part, on the pyroptotic activity of GSDME. The goals of this application are to define mechanisms underlying BRAFi + MEKi regulation of GSDME and pyroptosis in melanoma and to investigate how GSDME-induced pyroptosis alters the effects of immune checkpoint inhibitors. The standard of care for melanomas is immune checkpoint inhibition, specifically anti-PD-1 (pembrolizumab and nivolumab) and anti-CTLA-4 (ipilimumab). Immune checkpoint inhibitors are efficacious in some melanoma patients; however, many do not respond. Other patients who initially respond, ultimately progress. This proposal is designed to utilize targeted therapies to optimize up-front immune checkpoint inhibitors as well as invigorating the immune system in resistant tumors. Thus, we aim to develop new therapeutic strategies that will address clinical unmet needs in the melanoma field.

项目概要皮肤黑色素瘤的发病率正在上升。而小分子靶向抑制剂和免疫检查点抗体提高了晚期皮肤黑色素瘤的长期生存率，许多患者仍然没有受益，并且治疗方案与高毒性相关。我们正在研究决定因素黑色素瘤的治疗反应和耐药机制。根据我们的研究，我们的目标是生成预新组合的临床数据，可延迟/预防获得性耐药的发生，同时最大限度地减少患者的发病率毒性，以提高患者的生存率和生活质量。我们进行了多项临床试验工作（NCT03580382、NCT02012231、NCT02683395）。肿瘤免疫原性，定义为肿瘤免疫原性的能力肿瘤本身触发抗肿瘤适应性免疫反应，是最重要的决定因素之一。成功的抗癌治疗。肿瘤的免疫原性取决于其抗原性，由新抗原赋予抗原，以及由释放的损伤相关分子模式 (DAMP) 触发的佐剂效应在称为免疫原性细胞死亡（ICD）的过程中，受到应激或垂死的肿瘤细胞的影响。我们最近发现了一条信号通路，可以通过切换细胞凋亡从垂死细胞中有效释放 DAMP 转化为一种潜在的免疫原性细胞死亡形式，称为细胞焦亡。从机制上讲，caspase-3 的激活细胞凋亡过程中会导致gasdermin E (GSDME) 裂解，产生成孔的GSDME-N 片段。 GSDME-N 孔允许释放细胞内 DAMP，例如 HMGB1、DNA 和 ATP。有这个能力将细胞凋亡转变为焦亡的新途径表明 GSDME 诱导的焦亡可能是关键癌细胞免疫原性的效应器，并可能决定它们对各种抗癌药物的成功反应疗法。支持这一假设的是，我们的初步数据显示，有效的 BRAFi + MEKi 诱导的抗黑色素瘤细胞中的肿瘤免疫反应至少部分依赖于焦亡活性 GSDME。该应用程序的目标是定义 BRAFi + MEKi 监管的基础机制 GSDME 和黑色素瘤中的焦亡，并研究 GSDME 诱导的焦亡如何改变免疫检查点抑制剂。黑色素瘤的治疗标准是免疫检查点抑制，特别是抗 PD-1（pembrolizumab 和 nivolumab）和抗 CTLA-4（ipilimumab）。免疫检查点抑制剂是对某些黑色素瘤患者有效；然而，许多人没有回应。其他最初有反应的患者，最终取得进展。该提案旨在利用靶向疗法来优化前期免疫检查点抑制剂以及增强耐药肿瘤的免疫系统。因此，我们的目标是开发新的治疗策略将解决黑色素瘤领域临床未满足的需求。