Clinical implications for mtyrosine, an isomer of ptyrosine, for the treatment of aggressive prostate tumors

GUERON, GERALDINE; ANSELMINO, NICOLÁS; CHIARELLA, PAULA; ORTIZ, EMILIANO; PAEZ, ALEJANDRA VERÓNICA; GIUDICE, JIMENA ; SCHUSTER, FEDERICO; LEONARDI, DAIANA BEATRIZ; JAWORSKI, FELIPE MARTIN; LABANCA, ESTEFANIA; MANZANO, VERONICA; COTIGNOLA, JAVIER; MEISS ROBERTO; D'ACCORSO, NORMA; NAVONE, NORA; RUGGIERO, RAUL; VAZQUEZ, ELBA

Congreso; AACR Annual Meeting 2016; 2016

Clinical and experimental evidence suggest that primary tumors may exert a controlling action on its metastases. The phenomenon, by which atumorbearinghost is resistant to the growth of secondary tumor implants and metastasis, is known as concomitant tumor resistance (CR).We have previously showed in murine Tlymphoma(LB) tumors, that metatyrosine(mTyr)an isomer of tyrosine not present in normalproteins, is the main serum antitumoralfactor responsible for CR. In this work, we assess for the first time the CR phenomenon in humanprostate cancer (PCa). Athymic nude mice were inoculated with PC3 cells (primary implant) and after 14 days the animals received a secondinoculation (secondary implant). Strikingly, the growth of the secondary implant was significantly reduced after 27 days, in animals carrying theprimary xenograft. When phenylalanine (Phe), a protective amino acid highly present in primary tumors, and precursor of ptyrosine,wasperiodically inoculated at the site of a secondary tumor implant (otherwise inhibited by CR), this secondary implant grew similarly to controls.On the contrary, when mTyrwas inoculated at the site of a primary tumor implant or systemically, this implant did not grow. Tumor inhibitionwas associated with low expression of Ki67and STAT3.In vitro analyses demonstrate the higher inhibitory activity of the serum from tumorbearingmice on PC3 cell proliferation, compared to serumfrom control animals. mTyrcould account for most of the growthinhibitoryactivity present in the serum. Furthermore, we observed anincrease in the frequency of Gr1+ CD11b+ MDSCs in bone marrow, spleen and lymph nodes from tumorbearingmice compared to controlmice. This expansion correlated with a significantly higher production of reactive oxygen species and enhanced suppressor function uponCD8+ T cell proliferation. Further, in vitro studies also showed that exposure of PC3 cells to mTyrinhibited cell growth, induced G0/G1 cellcycle arrest, altered the expression levels of survivin, Ki67 and Hes1; impaired the NFκB/STAT3 pathway and induced autophagy; effectsreversed by Phe treatment. Strikingly, mTyrperiodic intravenous administration provoked a dramatic reduction of experimental lungmetastases generated in mice bearing PC3 human tumors. Altogether, we demonstrate for the first time that RC occurs in experimental humansolid tumors, that this effect is mediated by mTyr,a noncytotoxicmetabolite with high potential clinical implications for metastatic PCa.