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LP2, a cyclic angiotensin-(1-7) analog extended with an N-terminal D-lysine, impairs growth of patient-derived xenografts of colorectal carcinoma in mice

Published date

February 1, 2023

Abstract


"LP2 is a 4, 7 D, L lanthionine-stabilized analog of angiotensin-(1-7), with an N-terminal D-lysine, resistant to breakdown by peptidases. It is a specific agonist of the angiotensin II type 2 receptor. Consistent with its high specificity and stability, LP2 has shown excellent safety and pharmacokinetics in a first-in-human clinical phase Ia trial. Here, based on strong rationales, we studied the capacity of LP2 to inhibit the growth of patient-derived xenografts of colorectal cancer in mice. Prior to efficacy studies, immunohistochemistry on an untreated tissue array demonstrated that the AT2R expression is reduced in human colorectal cancer and in stroma when compared to tumor adjacent tissue. Subsequent studies demonstrated that LP2 at a subcutaneously injected dose as low as 0.2 µg/kg/day inhibited patient-derived xenografts of colorectal carcinoma in mice. Kinome analyses and validation of elected kinase inhibition indicated that LP2-mediated AT2R stimulation inhibited PI3K/AKT/mTOR which resulted in apoptosis via CDKs. LP2 acted synergistically with 5-FU and the EGFR inhibitor erlotinib. Taken together, the extremely low dose of LP2 at which antitumor activity is exerted, the synergism with selected drugs and, together with its excellent specificity, safety and stability, warrant further evaluation of LP2's inhibitory potential of colorectal cancer."

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