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Ceramide-Rich Platforms Functionalize Gemcitabine Uptake

富含神经酰胺的平台可功能化吉西他滨的摄取

基本信息

批准号：
10323269
负责人：
Richard N Kolesnick
金额：
$ 39.68万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10323269
关键词：
Angiogenesis Inhibitors Apoptosis Apoptotic Award Biology Cell Death Cell membrane Cells Ceramides Chemoresistance Chemosensitization Clinical Trials Cytidine DC101 Monoclonal Antibody Data Diffusion Dose Endothelial Cells Endothelium Engineering Equilibrative Nucleoside Transporter 1 Etoposide Extracellular Space Failure Gene Delivery Grant Histology Hydrolase Hydrolysis Implant Investigation KDR gene Lysosomes Mammalian Cell Manufacturer Name Mediating Membrane Memorial Sloan-Kettering Cancer Center Mus Nucleoside Transporter Nucleosides Outcome Paclitaxel Pharmaceutical Preparations Pharmacology Proliferating Proteins Radiation Radiation therapy Reagent Resistance Rights Role Schedule Services Signal Transduction Site Soft tissue sarcoma Sphingolipids Sphingomyelins Technology Testing Therapeutic Tyrosine Kinase Inhibitor Validation Vascular Endothelial Growth Factors Vegf inhibition Xenograft procedure acid sphingomyelinase analog antagonist anti-cancer base bevacizumab cancer therapy cell injury chemosensitizing agent chemotherapy design follow-up gemcitabine gene therapy improved in vivo inhibitor nanoliposome neoplastic cell phase II trial preclinical study prevent programs response sarcoma symposium tumor uptake

项目摘要

Our data indicate that in select settings activation of acid sphingomyelinase (ASMase)/ceramide signaling in tumor endothelial cells by radiation and certain chemotherapies synergizes with direct tumor cell damage to impact outcome. ASMase is a lysosomal hydrolase preferentially expressed in endothelial cells up to 20-fold compared with other mammalian cells. Mechanistically, endothelial ASMase activation leads within min to formation of plasma membrane ceramide-rich platforms (CRPs), macrodomains that organize apoptotic signaling programs. Support for our concept derives from studies showing xenografts of all histologies, when implanted in asmase-/- host mice become resistant to gemcitabine, paclitaxel, etoposide, and high single dose radiotherapy, effects reversed by exclusive adenoviral asmase gene delivery to tumor microvasculature. We recently discovered VEGF is the principal inhibitor of endothelial ASMase, and that anti-angiogenic drugs de-repress ASMase, amplifying tumor responses to anti-cancer therapies, but only under specific conditions. We found irrespective of t1/2 or anti-angiogenic class, these drugs enhance endothelial apoptosis and tumor response only if scheduled at 1-2h preceding chemotherapy, as ASMase can be de-repressed for only 1-2h. Based on these data, the MSK Sarcoma Service performed a Phase II trial that showed sphingolipid-based timing of bevacizumab vs. conventional synchronous timing improved metastatic sarcoma response to the cytidine analogue gemcitabine from 38 to 93% (p=0.0024; Tap and Kolesnick, unpublished). The current application will help establish the mechanism by which temporal delivery of a short-acting anti-angiogenic drug simultaneously enhances gemcitabine-induced endothelial and tumor cell apoptosis. The overarching hypothesis of this application is that the principal nucleoside transporter in mammalian cells, ENT1, required for gemcitabine uptake, is not constitutively “on” as generally accepted but must insert into CRPs on endothelial and tumor cells for functionalization. This new membrane-based mechanism of gemcitabine action will be explored in 3 aims designed to examine mechanism of ENT1 functionalization via CRPs in both endothelial and sarcoma cells, VEGF inhibition of ASMase-generated CRPs, and pharmacologic strategies to enhance endothelial ASMase- ceramide signaling in vivo to improve ENT1-mediated gemcitabine uptake and cell death. A major concept to be explored is that gemcitabine-induced ASMase secreted by endothelium triggers “bystander” gemcitabine uptake via ENT1 in tumor cells. As such, these investigations potentially define failure to stimulate ASMase/ceramide signaling as mediating a new form of chemoresistance. It is anticipated that information derived from studies proposed here will inform a planned follow up clinical trial for advanced sarcoma to be performed by the Sarcoma Service at MSK.

我们的数据表明，在特定环境下，酸性鞘磷脂酶 (ASMase)/神经酰胺信号的激活放疗和某些化疗对肿瘤内皮细胞产生协同作用，对肿瘤细胞产生直接损伤影响结果。 ASMase 是一种溶酶体水解酶，在内皮细胞中优先表达高达 20 倍与其他哺乳动物细胞相比。从机制上讲，内皮 ASMase 激活会在几分钟内导致质膜富含神经酰胺的平台（CRP）的形成，即组织细胞凋亡信号传导的宏结构域程序。对我们概念的支持来自于研究显示，当植入时，所有组织学的异种移植物 asmase-/-宿主小鼠对吉西他滨、紫杉醇、依托泊苷和高单剂量放疗产生耐药性，通过将独特的腺病毒 asmase 基因递送至肿瘤微血管系统来逆转效应。我们最近发现 VEGF 是内皮 ASMase 的主要抑制剂，抗血管生成药物可以解除抑制 ASMase，放大肿瘤对抗癌疗法的反应，但仅限于特定条件下。我们发现无论 t1/2 或抗血管生成类别如何，这些药物仅增强内皮细胞凋亡和肿瘤反应如果安排在化疗前 1-2 小时，因为 ASMase 只能解除抑制 1-2 小时。基于这些根据数据，MSK 肉瘤服务中心进行了一项 II 期试验，结果显示基于鞘脂的时间贝伐珠单抗与传统同步计时相比改善了转移性肉瘤对胞苷的反应类似物吉西他滨从 38% 增加到 93%（p=0.0024；Tap 和 Kolesnick，未发表）。当前的应用程序将帮助建立同时短暂递送短效抗血管生成药物的机制增强吉西他滨诱导的内皮细胞和肿瘤细胞凋亡。本研究的总体假设应用是哺乳动物细胞中的主要核苷转运蛋白 ENT1，是吉西他滨所需的摄取，并不像普遍接受的那样本质上“开启”，而是必须插入内皮细胞和肿瘤细胞上的 CRP 中用于功能化。这种新的基于膜的吉西他滨作用机制将在三个目标中进行探索旨在检查内皮细胞和肉瘤细胞中通过 CRP 进行 ENT1 功能化的机制， VEGF 对 ASMase 生成的 CRP 的抑制，以及增强内皮 ASMase 的药理学策略体内神经酰胺信号传导可改善 ENT1 介导的吉西他滨摄取和细胞死亡。一个重要的概念是探索的是吉西他滨诱导的内皮细胞分泌的 ASMase 触发“旁观者”吉西他滨摄取通过肿瘤细胞中的 ENT1。因此，这些研究可能会定义刺激 ASMase/神经酰胺的失败信号传导介导一种新形式的化学耐药性。预计来自研究的信息这里提出的建议将为肉瘤组织计划进行的晚期肉瘤后续临床试验提供信息 MSK 斯隆的服务。