Efficacy of targeted therapy and modeling androgen-receptor/HER2 signal pathways in preclinical salivary duct carcinoma models

临床前唾液管癌模型中靶向治疗和雄激素受体/HER2信号通路建模的疗效

• 批准号: 539250008
• 负责人: Dr. Marcel Mayer
• 金额: --
• 依托单位: Memorial Sloan Kettering Cancer Center
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/539250008?language=en
• 关键词: Efficacy; targeted; therapy; modeling; androgen

Objective 1 is to test the hypotheses that (1) AR and HER2 pathways have salivary gland cell-specific downstream effects with crosstalk between these two pathways, and that (2) the efficacy of antiandrogen therapy is testosterone-dependent in salivary duct carcinoma (SDC). We will perform comprehensive proliferation and transcriptomic experiments in SDC patient-derived xenograft (PDX) models with differing HER2 and AR expression to further characterize and understand the tumor-intrinsic and microenvironmental effects of AR and HER2 activation. This basic understanding of AR and HER2 pathways in SDC cells is crucial for the development of more effective therapeutic strategies. Objective 2 is to characterize the extent and intensity of expression of Trop-2, Mucin-1, and CD138 in the existing SDC PDXs and to examine the efficacy of sacituzumab govitecan, AS140, and indatuximab ravtansin in these preclinical models. The proof of in vivo antitumor efficacy will provide the basis for first clinical studies of these drugs in patients with SDC.

目标 1 是检验以下假设：(1) AR 和 HER2 通路具有唾液腺细胞特异性下游效应，且这两条通路之间存在串扰；(2) 抗雄激素治疗在唾液管癌 (SDC) 中的疗效依赖于睾酮。我们将在具有不同 HER2 和 AR 表达的 SDC 患者来源的异种移植 (PDX) 模型中进行全面的增殖和转录组实验，以进一步表征和了解 AR 和 HER2 激活对肿瘤内在和微环境的影响。对 SDC 细胞中 AR 和 HER2 通路的基本了解对于制定更有效的治疗策略至关重要。目标 2 是表征现有 SDC PDX 中 Trop-2、Mucin-1 和 CD138 表达的程度和强度，并检查 sacituzumab govitecan、AS140 和 indatuximab ravtansin 在这些临床前模型中的功效。体内抗肿瘤功效的证明将为这些药物在 SDC 患者中的首次临床研究提供基础。