BAD磷酸化抑制剂联合紫杉类药物针对难治乳腺癌的治疗评估及机制研究

乳腺癌是女性最常见的恶性肿瘤，大约70%属于雌激素受体阳性（ER+）。内分泌治疗是ER+乳腺癌的主要治疗手段，可有效改善生存率。他莫昔芬（TAM）是最成功且最广泛使用的内分泌治疗药物。然而，TAM耐药给乳腺癌的治疗带来了极大的挑战。化疗可用于乳腺癌患者术前或术后的辅助治疗，也是TAM耐药后的替代治疗方案。紫杉类是乳腺癌最常使用的化疗药物，但在临床上存在平衡大剂量毒副作用和小剂量耐药的难题。BAD磷酸化水平可以通过调节细胞凋亡从而影响肿瘤细胞存活。前期研究显示乳腺癌TAM耐药中BAD磷酸化上升。因此，我们提出联合紫杉类药物和BAD磷酸抑制剂可以恢复乳腺癌对TAM敏感性的科学假说。基于前期研究，我们将探究BAD磷酸化抑制剂NCK 联合紫杉类药物在TAM耐药ER+乳腺癌中联合使用的有效性和作用机制，并探究联合免疫治疗的可行性。本课题研究成果将为内分泌耐药ER+乳腺癌提供更精准和更有效的治疗策略。

Breast cancer (BC) is the most prevalent cancer and the leading cause of cancer death among women worldwide. More than 70% of breast cancers are ER-positive (+), which is defined by the presence of ER or PR with lack of HER2 gene overexpression. Endocrine therapy, a major modality in the treatment of ER+BC, has greatly improved the disease outcomes. Tamoxifen (TAM) therapy is one of the most widely and successfully used endocrine treatments. However, resistance to TAM has been a major challenge to BC treatment. Chemotherapy can be given before surgery (neoadjuvant) or after surgery (adjuvant) to BC patients. Taxanes are the most commonly used cytotoxic agents in BC treatment, which is also the well-established alternative treatment after tamoxifen resistance. Despite its efficacy, the balancing of efficacy with toxicity and resistance are the major issues associated with taxanes. Our previous result has shown that TAM resistance in BC is associated with the increase in BAD Ser99 phosphorylation. Research has also shown that taxanes treatment is associated with the upregulation of BAD phosphorylated protein at Serine 75 and 99 residues. Therefore, we hypothesized that the combination of taxanes with BAD phosphorylation inhibitor can sensitize the tumour cells to the treatments. From the published derivatives of bad phosphorylation inhibitor NPB, we generated and screened a novel derivative, NCK, which possess improved efficacy and bioavailability. In this investigation we will carry out preclinical evaluation and verification of the effect, mode of mechanism and clinical utility of NCK, inhibitor of BAD Ser99 phosphorylation in combination with taxanes in mammary tumour associated with ER+ subtypes with TAM resistance. Furthermore, we will investigate the immune response induced by combination treatment to identify the possibility for their further combination with immune therapy. Current project findings will provide the personalized and more efficacious therapeutic strategies that may overcome the acquired endocrine therapy resistance in ER+BC.