Abstract 4717: Clinical implications for m-tyrosine, an isomer of p-tyrosine, for the treatment of aggressive prostate tumors
Authors: Gueron Geraldine , Anselmino Nicolás , Chiarella Paula , Ortiz Emiliano , Paez Alejandra , Giudice Jimena , Schuster Federico , Leonardi Daiana , Jaworski Felipe , Labanca Estefania , Manzano Verónica , Cotignola Javier , Meiss Roberto , D′Accorso Norma , Navone Nora , Ruggiero Raul , Vazquez Elba 
Published: July 2016

Abstract
Clinical and experimental evidence suggest that primary tumors may exert a controlling action on its metastases. The phenomenon, by which a tumor-bearing host is resistant to the growth of secondary tumor implants and metastasis, is known as concomitant tumor resistance (CR).
We have previously showed in murine T-lymphoma (LB) tumors, that meta-tyrosine (m-Tyr) an isomer of tyrosine not present in normal proteins, is the main serum anti-tumoral factor responsible for CR. In this work, we assess for the first time the CR phenomenon in human prostate cancer (PCa). Athymic nude mice were inoculated with PC3 cells (primary implant) and after 14 days the animals received a second inoculation (secondary implant). Strikingly, the growth of the secondary implant was significantly reduced after 27 days, in animals carrying the primary xenograft. When phenylalanine (Phe), a protective amino acid highly present in primary tumors, and precursor of p-tyrosine, was periodically inoculated at the site of a secondary tumor implant (otherwise inhibited by CR), this secondary implant grew similarly to controls. On the contrary, when m-Tyr was inoculated at the site of a primary tumor implant or systemically, this implant did not grow. Tumor inhibition was associated with low expression of Ki-67 and STAT3.
In vitro analyses demonstrate the higher inhibitory activity of the serum from tumor-bearing mice on PC3 cell proliferation, compared to serum from control animals. m-Tyr could account for most of the growth-inhibitory activity present in the serum. Furthermore, we observed an increase in the frequency of Gr1+ CD11b+ MDSCs in bone marrow, spleen and lymph nodes from tumor-bearing mice compared to control mice. This expansion correlated with a significantly higher production of reactive oxygen species and enhanced suppressor function upon CD8+ T cell proliferation. Further, in vitro studies also showed that exposure of PC3 cells to m-Tyr inhibited cell growth, induced G0/G1 cell cycle arrest, altered the expression levels of survivin, Ki67 and Hes1; impaired the NFκB/STAT3 pathway and induced autophagy; effects reversed by Phe treatment. Strikingly, m-Tyr periodic intravenous administration provoked a dramatic reduction of experimental lung metastases generated in mice bearing PC3 human tumors. Altogether, we demonstrate for the first time that RC occurs in experimental human solid tumors, that this effect is mediated by m-Tyr, a non-cytotoxic metabolite with high potential clinical implications for metastatic PCa.
Citation Format: Geraldine Gueron, Nicolás Anselmino, Paula Chiarella, Emiliano Ortiz, Alejandra Paez, Jimena Giudice, Federico Schuster, Daiana Leonardi, Felipe Jaworski, Estefania Labanca, Verónica Manzano, Javier Cotignola, Roberto Meiss, Norma D′Accorso, Nora Navone, Raul Ruggiero, Elba Vazquez. Clinical implications for m-tyrosine, an isomer of p-tyrosine, for the treatment of aggressive prostate tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4717.