Sphingolipid-Based Anti-Angiogenic Chemosensitization

基于鞘脂的抗血管生成化学增敏

• 批准号: 9274265
• 负责人: Richard N Kolesnick
• 金额: $ 22.37万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-16 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274265
• 关键词: Angiogenesis Inhibitors; Apoptosis; Biology; Cell membrane; Cells; Ceramide Signaling Pathway; Ceramides; Chemosensitization; Clinical; Clinical Data; Clinical Trials; Data; Dose; Endothelial Cells; Endothelium; Engineering; Etoposide; Gene Delivery; Genetic Transcription; Goals; Half-Life; Histology; Implant; Lipids; Mediating; Memorial Sloan-Kettering Cancer Center; Mus; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Production; Radiation therapy; Refractory; Repression; Resistance; Schedule; Services; Signal Pathway; Signal Transduction; Soft tissue sarcoma; Sphingolipids; Testing; Therapeutic; Work; Xenograft procedure; acid sphingomyelinase; base; bevacizumab; cell injury; chemotherapy; design; follow-up; gemcitabine; improved; inhibitor/antagonist; neoplastic cell; phase 2 study; phase II trial; pre-clinical; programs; public health relevance; radiation response; response; sarcoma; tumor; vector

 DESCRIPTION (provided by applicant): Our pre-clinical data indicate that in specific settings activation of the acid sphingomyelinase (ASMase)/ceramide signaling pathway in tumor endothelial cells in response to radiation and certain chemotherapies synergizes with direct tumor cell damage to significantly impact overall tumor response, a concept which differs from the conventional paradigm that response to these therapies is tumor parenchymal cell autonomous. Mechanistically, ASMase activation leads within sec to min to formation of plasma membrane ceramide-rich platforms (CRPs), macrodomains that organize downstream effector signaling programs leading to endothelial apoptosis. Strong support for our concepts derives from studies of xenografts of all histologies, which when implanted in asmase-/- host mice become highly resistant to gemcitabine, paclitaxel, etoposide, and high single dose radiotherapy (SDRT). Further, we recently discovered VEGF is the principal inhibitor of endothelial ASMase, and that anti-angiogenic drugs de-repress ASMase amplifying tumor response to SDRT and select chemotherapies, but only under specific conditions. In pre-clinical models, we find that irrespective of half-life or anti-angiogenic class, these drugs enhance endothelial apoptosis and tumor response only if scheduled 1-2 h preceding chemotherapy, because ASMase can be de-repressed for only 1-2 h. Based on these data, the MSK Sarcoma Service performed a Phase II trial that showed sphingolipid-based timing of the anti-angiogenic bevacizumab as opposed to conventional timing improved tumor response of metastatic sarcoma from 38 to 93% (p=0.0024). We now seek to build upon these promising results to test the hypothesis that a short-acting anti-angiogenic is better suited for repeated cycles of chemosensitization of ASMase signaling compared to agents engineered for long-term VEGF suppression. Successful study completion will directly impact follow-up sarcoma clinical trials of sphingolipid-based anti-angiogenic chemosensitization.

 DESCRIPTION (provided by applicable): Our pre-clinical data indicating that in specific settings activation of the acid sphingomyelinase (ASMase)/ceramide signaling pathway in tumor endothelial cells in response to radiation and certain chemotherapies synergizes with direct tumor cell damage to significantly impact overall tumor response, a concept which differs from the conventional paradigm that response to these therapies is tumor paranchymal cell autonomous.从机械上讲，ASMase激活在SEC内导致最小内部形成质膜富含神经酰胺的平台（CRP），宏观域，组织下游效应子信号传导程序，导致内皮细胞凋亡。对我们概念的强烈支持来自对所有组织学的研究，当将其植入ASMase - / - 宿主小鼠时，它们对吉西他滨，紫杉醇，依托托戴哌辛和高剂量放射治疗（SDRT）具有高度抗性。此外，我们最近发现VEGF是内皮ASMase的主要抑制剂，并且抗血管生成药物会消除对SDRT和选择化学疗法的肿瘤反应的抑制作用ASMase，但仅在特定条件下。在临床前模型中，我们发现不论半衰期或抗血管生成类别，这些药物只有在化学疗法前1-2 h时才可以增强内皮细胞凋亡和肿瘤反应，因为ASMase只能在1-2小时内脱离aSMase。基于这些数据，MSK肉瘤服务进行了II期试验，该试验显示了基于鞘脂的抗血管生成bevacizumab的时机，而不是常规时机改善转移性肉瘤的肿瘤反应从38％到93％（p = 0.0024）。现在，我们试图建立这些承诺结果，以检验以下假设：与为长期抑制VEGF抑制的试剂相比，与ASMase信号的反复循环更适合反复的ASMase信号化学效应。成功的研究完成将直接影响基于鞘脂的抗血管生成化学敏化的随访肉瘤临床试验。

项目成果

Gemcitabine kills proliferating endothelial cells exclusively via acid sphingomyelinase activation.

吉西他滨仅通过酸性鞘磷脂酶激活来杀死增殖的内皮细胞。

• DOI: 10.1016/j.cellsig.2017.02.021
• 发表时间: 2017
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: vanHell,AlbertJ;Haimovitz-Friedman,Adriana;Fuks,Zvi;Tap,WilliamD;Kolesnick,Richard
• 通讯作者: Kolesnick,Richard