Gert Moll

Molecular Genetics

Lanthipeptide engineering:Therapeutic and Preventive Potential of Agonists of GAL2R and AT2R in Cancer

Aim: Do agonists of Gal2R and AT2R inhibit tumor growth and are they safe? Rationales: 1) Gal2R- related cell cycle arrest and apoptosis of cancer cells, 2) four AT2R-interacting tumor-suppressing proteins. Methods: M89b, a lanthipeptide agonist of Gal2R, or LP2, a lanthipeptide agonist of AT2R, were subcutaneously administered to mice bearing patient-derived xenografts (PDX) of tumors followed by mode of action studies. In vitro studies involving multi-target panels of pharmacologically relevant targets were used to assess safety. LP2 was subjected to full preclinical and clinical Phase Ia safety studies. Results: M89b inhibited tumor growth of a pancreatic ductal adenocarcinoma (PDAC) PDX depending on the level of expression of Gal2R, ranging to full inhibition at high Gal2R, to no inhibition without Gal2R. The M89b treatment of the high GAL2R PDAC-PDX-bearing mice diminished the expression of RacGap1 (p < 0.05), PCNA (p < 0.01), and MMP13 (p < 0.05). M89b enhances expression of GAL2R indicating preventive potential. LP2 alone partially inhibited patient-derived xenografts of colorectal carcinoma in mice and acted synergistically with 5-FU and the EGFR inhibitor erlotinib. Kinome analyses and validation indicated that LP2-mediated AT2R stimulation inhibited PI3K/AKT/mTOR which resulted in apoptosis via CDKs. LP2 restored blood platelet levels in gemcitabine-treated mice and countered anemia in tumor-bearing mice treated with erlotinib. Hence, LP2 has both antitumor and myeloprotective action. Preclinical M89b and clinical LP2 studies demonstrated excellent safety. Conclusion: agonists of GAL2R and AT2R have therapeutic potential and data prompt the hypothesis that they may prevent the emergence of pancreatic and colorectal cancer.