p53 mRNA rescue of tumor suppressor function prevents tumor growth and restores PARPi sensitivity in p53-deficient cancers in vitro and in vivo

Background: Loss of function in tumor suppressor genes is commonly associated with the onset/progression cancer and development therapeutic resistance. The p53 mutations resulting loss are common across variety tumors control cell proliferation more than 50% cancers. P53 null present about 10% driven However, to date there no effective treatment for rescuing We have developed a new potent strategy combing mRNA selective nanocarrier, rescue as potential approach Methods: ADGN-technology based on short amphipathic peptides that form stable neutral nanoparticles mRNA. ADGN-531 containing full length p53-mRNA were evaluated 20 different lines (osteosarcoma, pancreas, colorectal, ovarian, lung, breast prostate cancers) harboring types (null, deletion, nonsense, missense). Cell proliferation, cycle level apoptosis activation determined by flow cytometry, Elisa Tunel assay. In-vivo efficacy IV-administered (0.5 mg/kg) was colorectal SW403 (p53 deleted) osteosarcoma SaOs2 null) mouse xenografts. Sensitivity Veliparib (PARPi) following vitro PARPI resistant SUM-149PT OVCAR-8 cells PARPi sensitive MDA-MB436 cells. Results: NPs markedly delay growth large panel p53-null or nonsense mutations, inducing arrest G1 due p21 upregulation PUMA activation. demonstrated mediated directly correlated type mutation induces 60% 80% inhibition mutated missense Intravenous-administration wild resulted 90% 70% xenografted model, respectively. treatments well tolerated, without clinical toxicity inflammatory response. improves (200 fold) restores sensitivity ovarian veliparib. Conclusions: functions both vivo. Our study provides proof-of-concept restoration NP targeted delivery could be combined together other therapies combinatorial treatment. No conflict interest.