Targeting the MUC1-C Oncoprotein in Triple-Negative Breast Cancer

粘蛋白1（MUC 1）在约90%的人类乳腺癌中异常过表达，包括三阴性乳腺癌。 （TNBC）亚型，并且与较差的无进展生存期和总生存期相关。因此，MUC 1出现了 作为治疗TNBC的高度有吸引力的靶点;然而，迄今为止，还没有批准的针对 这种异二聚体跨膜蛋白。因此，现在需要的是开发新型药剂 靶向MUC 1，特别是MUC 1-C亚基，用于治疗难治性TNBC患者。 MUC 1由两个亚基组成：从细胞脱落的细胞外N-末端粘蛋白亚基（MUC 1-N 表面，和一个跨膜C-末端亚基（MUC 1-C）是致癌的。MUC 1-C作为一种 作为整合与转化相关的信号通路的节点，通过这种方式， MUC 1-C驱动（i）上皮-间充质转化（EMT），（ii）癌症干细胞（CSC）状态，（iii） 致瘤性，（iv）代谢改变，（V）表观遗传编程，和（vi）TNBC细胞的免疫逃避。 我们的工作也证明了MUC 1-C是一个药物靶点。作为一种方法，我们已经产生了 针对非脱落MUC 1-C胞外域的一流单克隆抗体（MAb）。这些mab 已经提供了开发特异性靶向MUC 1的抗体-药物缀合物（ADC）的独特机会。 C在TNBC细胞的表面上。我们的单克隆抗体也在开发抗体- 依赖性细胞介导的细胞毒性（ADCC）和双特异性免疫治疗剂。 此外，我们已经开发了靶向MUC 1-C胞质结构域并抑制其致癌性的药物。 功能用GO-203抑制剂靶向MUC 1-C逆转EMT、CSC和致瘤性TNBC 表型。用GO-203靶向MUC 1-C也抑制TNBC细胞的免疫逃避，这表明GO-203可以抑制TNBC细胞的免疫逃避。 203可以与其他免疫疗法联合使用。这些发现和发展的高度 新的抗体共同支持MUC 1-C作为潜在的免疫调节剂的靶向作用 TNBC患者的治疗方法。 具体目的是：（1）研究靶向MUC 1-C胞外结构域的ADC对MUC 1-C胞外结构域的影响。 （2）开发用于靶向TNBC细胞上的MUC 1-C的ADCC和双特异性抗体; MUC 1-C胞质结构域与GO-203/NPs联合其它免疫治疗剂， 避免TNBC免疫逃避;和（4）分析TNBC样本的MUC 1-C表达和MUC 1-C的表达。 抑制性免疫微环境作为对MUC 1-C靶向剂的应答的度量。

Mucin 1 (MUC1) is aberrantly overexpressed in ~90% of human breast cancers, including the triple-negative (TNBC) subtype, and is associated with poor progression-free and overall survival. MUC1 has thus emerged as a highly attractive target for the treatment of TNBC; however, to date there are no approved agents against this heterodimeric transmembrane protein. Therefore, what is needed now is the development of novel agents that target MUC1 and specifically the MUC1-C subunit for the treatment of patients with refractory TNBC. MUC1 consists of two subunits: an extracellular N-terminal mucin subunit (MUC1-N) that is shed from the cell surface, and a transmembrane C-terminal subunit (MUC1-C) that is oncogenic. MUC1-C functions as an oncoprotein by acting as a node for integrating signaling pathways linked to transformation. In this way, MUC1-C drives (i) the epithelial-mesenchymal transition (EMT), (ii) the cancer stem cell (CSC) state, (iii) tumorigenicity, (iv) metabolic alterations, (v) epigenetic programming, and (vi) immune evasion of TNBC cells. Our work has also demonstrated that MUC1-C is a druggable target. As one approach, we have generated first-in-class monoclonal antibodies (MAbs) against the non-shed MUC1-C extracellular domain. These MAbs have provided a unique opportunity to develop antibody-drug conjugates (ADCs) that specifically target MUC1- C on the surface of TNBC cells. Our MAbs are also being advanced for the development of antibody- dependent cell-mediated cytotoxicity (ADCC) and bispecific immunotherapeutics. In addition, we have developed agents that target the MUC1-C cytoplasmic domain and inhibit its oncogenic function. Targeting MUC1-C with the GO-203 inhibitor reverses the EMT, CSC and tumorigenic TNBC phenotype. Targeting MUC1-C with GO-203 also inhibits immune evasion of TNBC cells, indicating that GO- 203 could be used in combination with other immunotherapies. These findings and the development of highly novel antibodies have collectively supported the targeting of MUC1-C as potential immunotherapeutic approaches for patients with TNBC. The Specific Aims are: (1) To investigate the effects of ADCs targeting the MUC1-C extracellular domain on TNBC cells; (2) To develop an ADCC and a bispecific antibody for targeting MUC1-C on TNBCs; (3) To target the MUC1-C cytoplasmic domain with GO-203/NPs in combination with other immunotherapeutics to circumvent TNBC immune evasion; and (4) To analyze TNBC specimens for MUC1-C expression and the suppressive immune microenvironment as metrics for response to MUC1-C-targeted agents.