Sphingolipid-Based Anti-Angiogenic Chemosensitization

 描述（由申请方提供）：我们的临床前数据表明，在特定情况下，肿瘤内皮细胞中酸性鞘磷脂酶（ASMase）/神经酰胺信号传导通路对放射和某些化疗的反应与直接肿瘤细胞损伤协同作用，从而显著影响总体肿瘤反应，这一概念不同于传统范式，即对这些治疗的反应是肿瘤实质细胞自主的。从机制上讲，ASMase激活在秒至分钟内导致质膜富含神经酰胺的平台（CRP）的形成，这些平台是组织下游效应物信号传导程序的大结构域，导致内皮细胞凋亡。对我们的概念的有力支持来自于所有组织学的异种移植物的研究，当移植到asmase-/-宿主小鼠中时，其对吉西他滨、紫杉醇、依托泊苷和高单剂量放疗（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去抑制ASMase放大肿瘤对SDRT和选择化疗的反应，但仅在特定条件下。在临床前模型中，我们发现，无论半衰期或抗血管生成类别如何，这些药物只有在化疗前1-2小时才能增强内皮细胞凋亡和肿瘤反应，因为ASMase只能去抑制1-2小时。基于这些数据，MSK Sarcoma Service进行了一项II期试验，该试验显示基于鞘脂的抗血管生成贝伐珠单抗给药时间与常规时间相比，转移性肉瘤的肿瘤缓解率从38%提高至93%（p=0.0024）。我们现在试图建立在这些有希望的结果，以测试的假设，短效抗血管生成更适合于反复周期的化疗敏感性ASMase信号相比，长期VEGF抑制工程的代理。研究的成功完成将直接影响基于鞘脂的抗血管生成化疗增敏的后续肉瘤临床试验。

 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.