TROP2介导代谢重编在三阴性乳腺癌发生发展中的机制及靶向治疗研究

三阴性乳腺癌（TNBC）是临床预后极差的乳腺癌亚型，亟需新的治疗方向及策略。申请人通过对乳腺癌组织微阵列检发现TROP2在TNBC中显著高表达，敲低TROP2蛋白水平显著抑制TNBC生长及转移，但具体机制尚不明确。蛋白组学结果发现敲低TROP2显著降低TALDO1代谢酶的表达，提示TROP2可能通过调控TALDO1的活性影响乳腺癌细胞代谢重编，从而促进TNBC的发生发展。同时前期申请人研发了16种新型抗TROP2抗体并初步证实其可显著抑制TNBC生长，未发现药物相关毒副作用。本项目将采用CHIP-qPCR揭示TROP2是否在转录水平调控TALDO1及关联代谢酶活性；通过敲低及过表达TALDO1明确TALDO1介导细胞重编对TNBC发生发展的影响；拟在细胞、动物及病人异种移植模型中探究新型抗TROP2抗体在TNBC靶向作用。将为TNBC患者提供基于肿瘤代谢学及分子生物学依据的治疗策略。

Breast cancer remains the second most lethal cancer among women world widely and triple negative breast cancer is the most aggressive subtype with limited treatment options. TROP2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. We demonstrate that TROP2 is overexpressed in triple negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC tumor growth supporting the oncogenic role of TROP2 in breast cancer. Through proteomic profiling, we discovered a novel metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK five metabolic reprogramming genes that was downregulated in Trop2-depleted breast cancer tumors. These findings provide a strong evidence that Trop2 may regulate TNBC metabolic reprogramming though those five genes. We generated a new agent, antibodies targeting TROP2, and demonstrated that the anti-TROP2 antibody significantly delays tumor growth of TNBC with no measurable toxicity. We hypothesize that the novel anti-TROP2 antibody represents a promising therapeutic strategy for TNBC. The major goals of the proposed projects are 1) to identify the mechanisms underlying TROP2 regulating metabolic reprogramming genes in TNBC; 2) to test novel anti-TROP2 antibody as a novel therapeutic strategy to target TNBC growth and metastasis. Successful completion of the proposed study will develop new targeted therapies for triple negative breast cancer and thus will have a significant clinical impact on improving the quality of life and extending the lifespan of patients with aggressive breast cancer.