Proteolysis-targeting chimera against BCL-XL inhibits breast cancer metastasis

项目摘要-摘要 转移是BrCa死亡的主要原因。大多数转移性BrCa（IV期）女性主要接受治疗 与全身治疗，如激素治疗（雌激素受体阳性BrCa），化疗，靶向 治疗和一些组合。目前的治疗方法不太可能治愈转移性BrCa， 诊断后5年内死亡率为70%。很大程度上缺乏靶向BrCa转移的治疗。这里我们 旨在开发具有双重靶向能力的单一药物：1）直接杀死转移性癌细胞; 2） 杀死癌症特异性调节性T细胞（TcR），从而诱导抗癌免疫。为了寻找 潜在的分子靶点，我们决定使用新兴的新型PROTAC技术抑制BCL-XL。具有两 我们最近开发的主要PROTAC化合物（BCL-XL-Ps），我们发现这两种化合物都可以 有效地导致BCL-XL在体外和体内的降解。有趣的是，BCL-XL-Ps似乎 在我们测试的所有同基因癌症模型中， 转移使用多学科技术，我们相信BCL-XL-Ps可以杀死转移性癌细胞和TcR。 正如我们最初预期的那样。当前的项目将定义BCL-XL在以下方面的特定谱系作用： 癌细胞和T细胞。即使直接的癌细胞杀伤可能不足以根除转移性癌细胞， 如初步数据所示，一部分死亡的癌细胞可以提供足够的自体或 用于T细胞活化的新抗原。此外，癌细胞中的BCL-XL耗尽使它们对CD 8-T细胞敏感。 中介杀人BCL-XL-Ps介导的Treg耗竭和T细胞的直接激活产生了强的抗-CD 45抗体。 可以用于癌症治疗的癌症免疫力。BCL-XL-Ps对BCL-XL的同时耗竭， 癌细胞进一步使它们对CD 8-T细胞介导的杀伤敏感。在这里，我们将研究的血统特定的作用， BCL-XL治疗癌症转化研究也得到了临床观察的有力支持， 蛋白质表达预测乳腺癌患者的生存期较短。我们的长期目标是发展 该先导化合物进入临床，用于癌细胞和TdR双重靶向治疗转移性乳腺癌。

Project Summary-Abstract Metastasis is the major cause of BrCa death. Most women with metastatic BrCa (stage IV) are treated mainly with systemic therapy such as hormone therapy (for estrogen receptor-positive BrCa), chemotherapy, targeted therapy, and some combinations. Current treatments are very unlikely to cure metastatic BrCa, with more than 70% death rate within 5 years of diagnosis. Therapeutic targeting BrCa metastasis is largely lacking. Here we are aiming to develop a single agent with dual targeting capability: 1) to kill metastatic cancer cells directly; 2) to kill cancer specific regulatory T cells (Tregs) hence inducing anti-cancer immunity. With an effort to search the potential molecular target, we decided to inhibit BCL-XL using an emerging novel PROTAC technology. With two lead PROTAC compounds (BCL-XL-Ps) we have recently developed, we found that both compounds can efficiently lead to the degradation of BCL-XL in vitro and in vivo. Interestingly, it appears that the BCL-XL-Ps work in all syngeneic cancer models we have tested with the strongest suppressive efficacy in breast cancer metastasis. Using multidisciplinary techniques, we believe BCL-XL-Ps kill metastatic cancer cells and Tregs simultaneously as we initially expected. The current project will define the lineage-specific role of BCL-XL in cancer cells and in Tregs. Even though the direct cancer cell killing may not be sufficient to eradicate metastatic tumor growth as shown in the preliminary data, a portion of dead cancer cells may provide sufficient auto- or neo-antigens for T cell activation. In addition, BCL-XL depletion in cancer cells sensitizes them to CD8-T cell mediated killing. The BCL-XL-Ps-mediated Treg depletion and direct activation of T cells elicits a strong anti- cancer immunity that can be harvested for cancer therapy. Simultaneous depletion of BCL-XL by BCL-XL-Ps in cancer cells further sensitize them to CD8-T cell mediated killing. Here we will study the lineage-specific roles of BCL-XL in cancer. The translational research is also strongly supported by clinical observations that BCL-XL protein expression predicts shorter patient survival in breast cancer patients. Our long-term goal is to develop the lead compound into clinic for dual targeting of cancer cells and Tregs in treating metastatic breast cancers.