Potent antitumor effects of cell-penetrating peptides targeting STAT3 axis

• Published in: JCI insight Vol. 6; no. 2
• Main Authors: Aftabizadeh, Maryam, Li, Yi-Jia, Zhao, Qianqian, Zhang, Chunyan, Ambaye, Nigus, Song, Jieun, Nagao, Toshikage, Lahtz, Christoph, Fakih, Marwan, Ann, David K, Yu, Hua, Herrmann, Andreas
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 25.01.2021; American Society for Clinical investigation
• Subjects: Acetylation; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell-Penetrating Peptides - chemistry; Cell-Penetrating Peptides - pharmacology; Cytokine Receptor gp130 - chemistry; Drug Design; HCT116 Cells; Humans; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Melanoma, Experimental - drug therapy; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Mice; Mice, Inbred C57BL; Oncology; Pancreatic Neoplasms - drug therapy; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Protein Multimerization; Proto-Oncogene Proteins c-myc - chemistry; Proto-Oncogene Proteins c-myc - pharmacology; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - chemistry; Therapeutics; Xenograft Model Antitumor Assays; Peptides; Oncology; Therapeutics
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.136176

To date, there are no inhibitors that directly and specifically target activated STAT3 and c-Myc in the clinic. Although peptide-based inhibitors can selectively block activated targets, their clinical usage is limited because of low cell penetration and/or serum stability. Here, we generated cell-penetrating acetylated (acet.) STAT3, c-Myc, and Gp130 targeting peptides by attaching phosphorothioated (PS) polymer backbone to peptides. The cell-penetrating peptides efficiently penetrated cells and inhibited activation of the intended targets and their downstream genes. Locally or systemically treating tumor-bearing mice with PS-acet.-STAT3 peptide at low concentrations effectively blocked STAT3 in vivo, resulting in significant antitumor effects in 2 human xenograft models. Moreover, PS-acet.-STAT3 peptide penetrated and activated splenic CD8+ T cells in vitro. Treating immune-competent mice bearing mouse melanoma with PS-acet.-STAT3 peptide inhibited STAT3 in tumor-infiltrating T cells, downregulating tumor-infiltrating CD4+ T regulatory cells while activating CD8+ T effector cells. Similarly, systemic injections of the cell-penetrating c-Myc and Gp130 peptides prevented pancreatic tumor growth and induced antitumor immune responses. Taken together, we have developed therapeutic peptides that effectively and specifically block challenging cancer targets, resulting in antitumor effects through both direct tumor cell killing and indirectly through antitumor immune responses.