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)的女性主要接受治疗 采用全身治疗，如激素治疗(针对雌激素受体阳性的BRCA)、化疗、靶向治疗 治疗，和一些组合。目前的治疗方法不太可能治愈转移性BRCA，有超过 确诊后5年内死亡率达70%。针对BRCA转移的治疗在很大程度上是缺乏的。在这里我们 正在致力于开发一种具有双重靶向能力的单剂：1)直接杀死转移的癌细胞；2) 杀死癌症特异性调节性T细胞(Tregs)，从而诱导抗癌免疫。努力搜索 为了寻找潜在的分子靶点，我们决定使用一种新兴的PROTAC技术来抑制bclxl。有两个人 我们最近开发的铅PROTAC化合物(BCL-XL-Ps)，我们发现这两种化合物都可以 在体外和体内均能有效地降解bclxl。有趣的是，BCL-XL-Ps似乎起作用 在所有同基因癌症模型中，我们测试的乳腺癌抑制效果最强 转移。利用多学科技术，我们相信bclxl-Ps杀死转移的癌细胞和Treg 与我们最初预期的同时。目前的项目将定义BCL-XL在 癌细胞和Tregs中。即使直接杀死癌细胞可能不足以根除转移 肿瘤生长如初步数据所示，部分死亡的癌细胞可能会提供足够的自体或 T细胞活化的新抗原。此外，癌细胞中bclxl的缺失使其对CD8-T细胞敏感 居间杀人。BCL-XL-Ps介导的Treg耗竭和直接激活T细胞诱导产生强烈的抗 可用于癌症治疗的癌症免疫力。BCL-XL-Ps同时耗尽BCL-XL的研究 癌细胞进一步使它们对CD8-T细胞介导的杀伤敏感。在这里，我们将研究血统特定的角色 BCL-XL在癌症中的表达。BCL-XL的临床观察也有力地支持了这项翻译研究 蛋白表达预测乳腺癌患者的患者生存期较短。我们的长远目标是发展 前导化合物进入临床用于肿瘤细胞和Tregs的双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.