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：
10543438
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/10543438
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 Mediating Membrane Memorial Sloan-Kettering Cancer Center Mus Nucleoside Transporter Nucleosides Outcome Paclitaxel Pharmaceutical Preparations Proliferating Proteins Radiation Radiation therapy Reagent Resistance Rights Role Schedule Services Signal Transduction Site Soft tissue sarcoma Sphingolipids Sphingomyelins Testing Therapeutic Tyrosine Kinase Inhibitor Validation Vascular Endothelial Growth Factors Vegf inhibition Xenograft procedure acid sphingomyelinase analog antagonist anti-cancer bevacizumab cancer therapy cell injury chemotherapy derepression design follow-up gemcitabine gene therapy improved in vivo inhibitor nanoliposome neoplastic cell pharmacologic phase II trial preclinical study prevent programs response sarcoma symposium synergism technology development treatment response tumor uptake

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 Mediating Membrane Memorial Sloan-Kettering Cancer Center Mus Nucleoside Transporter Nucleosides Outcome Paclitaxel Pharmaceutical Preparations Proliferating Proteins Radiation Radiation therapy Reagent Resistance Rights Role Schedule Services Signal Transduction Site Soft tissue sarcoma Sphingolipids Sphingomyelins Testing Therapeutic Tyrosine Kinase Inhibitor Validation Vascular Endothelial Growth Factors Vegf inhibition Xenograft procedure acid sphingomyelinase analog antagonist anti-cancer bevacizumab cancer therapy cell injury chemotherapy derepression design follow-up gemcitabine gene therapy improved in vivo inhibitor nanoliposome neoplastic cell pharmacologic phase II trial preclinical study prevent programs response sarcoma symposium synergism technology development treatment response tumor uptake

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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，在某些设置中激活酸鞘磷脂酶（ASMase）/神经酰胺信号传导肿瘤内皮细胞通过辐射和某些化学疗法与直接肿瘤细胞损伤协同至影响结果。 ASMase是一种溶酶体水解酶，最好在内皮细胞中表达20倍与其他哺乳动物细胞相比。从机械上讲，内皮ASMase激活导致最小内部的激活导致质膜富含神经酰胺平台（CRP）的格式，组织凋亡信号的宏观构胺程序。对我们的概念的支持来自于植入所有组织学的Xenographogrichics的研究 ASMASE - / - 宿主小鼠对吉西他滨，紫杉醇，依托托苷和高剂量放射疗法具有抗药性，腺病毒ASMase基因递送至肿瘤微脉管系统的效果逆转。我们最近发现的VEGF是内皮ASMase的主要抑制剂，并且抗血管生成药物会驱除抑制作用 ASMase，扩增肿瘤对抗癌疗法的反应，但仅在特定条件下。我们发现不论T1/2或抗血管生成类别，这些药物仅增强内皮细胞凋亡和肿瘤反应如果安排在化学疗法之前的1-2H时，则仅以1-2H的速度去除ASMase。基于这些数据，MSK肉瘤服务进行了II期试验，显示基于鞘脂的时间贝伐单抗与常规同步时机改善了cytidine的转移性肉瘤反应模拟吉西他滨从38％到93％（p = 0.0024; tap and kolesnick，未发表）。当前申请将帮助建立简单地暂时递送抗血管生成药物的机制增强吉西他滨诱导的内皮和肿瘤细胞凋亡。总体假设应用是吉西他滨所需的哺乳动物细胞中的主要核核苷转运蛋白吸收，不是作为普遍接受的组成性“ on”，而必须插入内皮细胞和肿瘤细胞上的CRP 用于功能化。这种新的基于膜的吉西他滨动作机制将在3个目标中探索旨在检查内皮细胞和肉瘤细胞中通过CRP官能化的机制， VEGF抑制ASMASE生成的CRP，以及增强内皮ASMase-的药物策略在体内神经酰胺信号传导改善ENT1介导的吉西他滨摄取和细胞死亡。一个主要的概念探索的是，吉西他滨诱导的ASMase由内皮触发者“旁观者” Gemcitabine摄取通过肿瘤细胞中的ENT1。因此，这些投资有可能定义未能刺激ASMase/Ceramide 信号传导是介导一种新形式的化学抗性。预计从研究中得出的信息此处提出的建议将告知计划的后续临床试验，以便由肉瘤进行高级肉瘤在MSK服务。