Bahaa Mustafa

About one-fourth of patients with pancreatic ductal adenocarcinoma (PDAC) are categorized as borderline resectable (BR) or locally advanced (LA). Chemotherapy and radiation therapy have not yielded the anticipated outcomes in curing patients with BR/LA PDAC. The surgical resection of these tumors presents challenges owing to the unpredictability of the resection margin, involvement of vasculature with the tumor, the likelihood of occult metastasis, a higher ratio of positive lymph nodes, and the relatively larger size of tumor nodules. Oncolytic virotherapy has shown promising activity in preclinical PDAC models. Unfortunately, the desmoplastic stroma within the PDAC tumor microenvironment establishes a barrier, hindering the infiltration of oncolytic viruses and various therapeutic drugs—such as antibodies, adoptive cell therapy agents, and chemotherapeutic agents—in reaching the tumor site. Recently, a growing emphasis has been placed on targeting major acellular components of tumor stroma, such as hyaluronic acid and collagen, to enhance drug penetration. Oncolytic viruses can be engineered to express proteolytic enzymes that cleave hyaluronic acid and collagen into smaller polypeptides, thereby softening the desmoplastic stroma, ultimately leading to increased viral distribution along with increased oncolysis and subsequent tumor size regression. This approach may offer new possibilities to improve the resectability of patients diagnosed with BR and LA PDAC.

Blockade of the interaction between programmed cell death ligand-1 (PD-L1) and its receptor PD-1 has shown great success in cancer immunotherapy. Peptides possess unique characteristics that give them significant advantages as immune checkpoint inhibitors. However, unfavorable physicochemical properties and proteolytic stability profiles limit the translation of bioactive peptides as therapeutic agents. Studies have revealed that cyclization improves the biological activity and stability of linear peptides. In this study, we report the use of macrocyclization scanning for the discovery of cyclic anti-PD-L1 peptides with improved bioactivity. The cyclic peptides demonstrated up to a 34-fold improvement in the PD-1/PD-L1 blocking activity and significant in vivo anti-tumor activity. Our results demonstrate that macrocyclization scanning is an effective way to improve the serum stability and bioactivity of the anti-PD-L1 linear peptide. This strategy can be employed in the optimization of other bioactive peptides, particularly those for protein-protein interaction modulation.