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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：
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

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，在选定的设置激活酸性鞘磷脂酶(ASMase)/神经酰胺信号