While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect. Albumin metabolism-mediated apoptosis triggered expression of caspase-3 allows the continuous activation of the PDC, accumulation of payloads, sustained upregulation of tumoral caspase-3, and intensified in-situ apoptosis. Importantly, PDC strategy exerts potent therapeutic efficacy against PTEN-loss metastatic triple-negative breast cancer, the highly aggressive and heterogenous nature of which remains a challenge conventional targeted therapies need to overcome. This study thus presents a conceptually novel approach to treat PTEN-loss cancer and creates new translational perspectives of exploiting PTEN-loss for providing an avenue to advance current targeted therapy.
|Publication status||Published - 2022 Oct|
Bibliographical noteFunding Information:
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea ( NRF ) grant funded by the Korea government ( MSIT ) (No. 2020R1A2C2015026 ) and supported by Korea Drug Development Fund funded by Ministry of Science and ICT , Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (No. HN21C0264 ). This research was also supported by the BK21 FOUR (Fostering Outstanding Universities for Research) funded by the Ministry of Education ( MOE , Korea) and National Research Foundation of Korea ( NRF ).
© 2022 The Authors
All Science Journal Classification (ASJC) codes
- Ceramics and Composites
- Mechanics of Materials