Despite the emergence of advanced therapeutics such as targeted therapy and immunotherapy in the modern oncology, cytotoxic chemotherapy still remains as the first-line treatment option in a wide range of cancers attributing to its potency. Many endeavors have been made to overcome the toxicity issues of cytotoxic chemotherapy by improving the specific delivery to the tumor, with active tumor targeting being one of the most popular approaches. However, such an approach has been challenged by the intratumor heterogeneity and the lack of valid molecular target in many types of cancer. Here, we introduce a novel albumin-binding prodrug MPD03 that could specifically deliver highly potent cytotoxin docetaxel to the tumor as an important component of chemotherapy for the treatment of triple-negative breast cancer (TNBC). MPD03 was synthesized by conjugating docetaxel to the C-terminus of the KGDEVD peptide via self-eliminating linker and introducing a maleimide group to the Lys sid chain of the peptide. MPD03 was able to bind albumin after administration via maleimide group for an extended circulation time and metabolized into docetaxel in tumor specific manner by reacting with the caspase-3 upregulated in tumor by apoptosis inducing agent, exerting a highly potent anticancer effect with good safety profile in TNBC xenograft model. PARP inhibitor olaparib was used in combination therapy with MPD03 in our strategy in terms of apoptosis inducer. Using our treatment regimen, we seek to expand our strategy to eradicate metastatic tumors.
Citation Format: Youngseok Cho, Harin Kim, Seung Woo Chung, Youngro Byun. Novel strategy for treatment of triple-negative breast cancer by highly potent caspase-cleavable docetaxel prodrug [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A08. doi:10.1158/1535-7163.TARG-19-LB-A08