Stimulation of antineoplastic potency of targeted therapeutic drugs in combination with NKp44-derived peptide studied in Tumor ex-vivo model

Abstract

Lung adenocarcinoma is one of the most common cancer worldwide with less than 30% of survival rate of nearly 5 years. In recent years, increasing understanding and characterization of cancer microenvironment resulted in the development of numerous cancer-specific targeted drugs as personalized medicine. Unfortunately, the lung cancer patient’s survival rate remains low. This work will strongly prove the concept of combinatorial treatment of PCNA inhibitor peptide and anti-cancer targeted drugs using the Tumor Ex VIVO Analysis (TEVA) model, which can predict patient-specific drug response. Four Patient-derived xenografts (PDXs) were employed for TEVA. PDX’s were cut into 2 x 2 x 2 mm³, explanted and treated with in-house designed PCNA targeting peptide, R11-NLS-pep8 (PEP8), combined with clinically resistant targeted therapeutic drugs based on genomics sequences for 24h. Results were analyzed by calculating TEVA Score based on immunohistochemistry staining of TUNEL and Ki67 (apoptosis and proliferation markers); showing that two patients out of four responded to the combination of PEP8 with targeted therapeutic drugs comparing to single treated explants. Response score for combinatorial treatment was 6 and 10 times more compared to the control whereas single treatment did not show a significant difference. In-Vivo experiments for LSE-Pt#1 resulted in suppression of the tumor growth after treating with PEP8 and targeted therapeutic drugs in combination. Overall our data provide new evidence that PCNA inhibitor peptide, PEP8, can enhance the efficiency of targeted therapeutic drugs for some patients.