多巴胺受体D1亚型介导的抗肿瘤机理及药物动力学/药效动力学研究

Drug resistance is one of the most important scientific issues remaining to be solved in cancer chemotherapy. Growing research indicates that eradicating cancer stem-like cells (CSCs) may become a promising strategy. Previous results suggested that dopamine receptor (DR) may serve as a potential therapeutic target of anti-CSCs therapies. Among all DR subtypes, D1DR and D2DR are the most-studied and widely distributed members. Agonists or Antagonists of D1DR or D2DR may possess different functions. To the best of our knowledge, there’s no study indicating whether D1DR-mediated pathway is involved in the CSCs-targeting mechanism. Based upon literature study and previous results, we assume that D1DR agonism is associated with anti-CSCs effects. The aim of our study is to investigate the in vitro and in vivo effects as well as the underlying mechanisms mediated by D1DR agonists on D1DR+/+ or D1DR-/- parent tumor cells and their corresponding CSCs, and to respectively establish a PK/PD model of D1DR agonists-SKF38393 and DA, which integrates D1DR expression, CSC frequency and tumor volume together. It is our expectation that the results from the proposed research projects will contribute to (1) providing a brand new target for anti-CSCs therapies, and to (2) quantitatively characterizing the function of D1DR activation in tumor progression, as well as to (3) offering important guidance for translational studies.

耐药性问题是肿瘤药物治疗中亟需解决的科学问题，靶向肿瘤干细胞（CSCs）是根治肿瘤的新策略。多巴胺受体（DR）可作为靶向CSCs的特异性靶点，DR家族的主要成员D1DR和D2DR的上调或下调可能会发挥不同的功能，目前尚未有人提出D1DR介导的通路是否具有抗肿瘤作用。本课题通过前期研究和文献调研提出假设：激动D1DR可靶向作用于CSCs。本研究拟通过考察D1DR激动剂作用于D1DR+/+和D1DR-/-型母代肿瘤细胞及对应CSCs的体内外药效和机理，以系统研究激动D1DR对CSCs的作用机制，为CSCs疗法提供新的治疗靶点；通过评价D1DR激动剂SKF38393和DA的药动学（PK）和药效学（PD）性质，建立整合D1DR表达量、瘤内CSC比例和肿瘤体积的PK/PD模型，定量说明D1DR激动在肿瘤进展过程中所发挥的作用，为D1DR激动剂靶向治疗CSCs提供量化标准，为转化研究提供重要参考。