Xiangyi Kong, MD. & PhD. | National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Jing Wang, MD. & PhD.; Yi Fang, MD. & PhD. ; Zhongzhao Wang, MD. & PhD; Xiangyu Wang, MD. & PhD; Wenxiang Zhang, MD. & PhD
Competition Sponsor: Chinese Academy of Medical Sciences
Awardee Year: 2022
Trastuzumab is an effective drug for the treatment of HER2-positive breast cancer, but the problem of drug resistance severely limits its clinical application. The applicant’s previous study found that lncRNA HOTTIP may mediate trastuzumab resistance by activating the Wnt signaling pathway and HOTTIP could be used as a new potential target to reverse this resistance. The present project intends to further explore the molecular mechanisms by which HOTTIP affects the Wnt pathway and thus mediates drug resistance at the cellular and animal levels from perspectives including RNA-binding proteins; on this basis, we will design and synthesize a nanomotor drug delivery system, PFC(si-HOTTIP/GOD)@MnO2, with multiple functions including delivering specific siRNA to inhibit HOTTIP, promoting tumor glucose deprivation/exhaustion, improving the hypoxic microenvironment, controllable actuation triggered by in vitro ultrasound, and real-time in situ drug release monitoring visualization. We will combine RNAi therapy, tumor starvation therapy, and microenvironmental oxygen therapy to provide a new treatment strategy for reversing trastuzumab resistance. We will investigate the nano-drug’s physical and chemical properties, pharmacological effects, anti-drug-resistance effects and mechanisms, and safety. This project is an in-depth expansion of the applicant’s preliminary research results supported by previous research funding, and has a good prospect of clinical transformation.
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