PROLACTIN AND ITS RECEPTOR AS THERAPEUTIC TARGETS IN GLIOBLASTOMA

ASAD, ANTONELA S; GONZALEZ, NAZARENO; SAGRIPANTI, SOFIA; NICOLA CANDIA, ALEJANDRO J; ZUCCATO, CAMILA; ORRILLO, SANTIAGO JORDI; ABT, ARACELI; ZANETTI, FLAVIA A.; PIDRE, MATIAS L.; ROMANOWSKI, VICTOR; GOFFIN, V.; SEILICOVICH, ADRIANA; PISERA, DANIEL ALBERTO; FERRARIS, MARÍA JIMENA; CANDOLFI, MARIANELA

New Orleans

Congreso; Society for Neuro-Oncology; 2018

Prolactin (PRL) has been detected in glioblastoma (GBM) biopsies and hyperprolactinemia has been observed in many GBM patients, which has a positive correlation with the proliferation index and the vascular density of brain tumors. Although PRL has been associated to the development of many hormone-dependent cancers, its role in the pathogenesis of GBM remains unknown. Our meta-analysis of transcriptomic data from the Cancer Genome Atlas (GSE4290) revealed that PRL is expressed in 12% of low grade gliomas (LLG) and 28% of GBM biopsies, and its receptor (RPRL) is present in virtually all LLG and GBM samples. We detected expression of PRL and RPRL in all human and murine GBM cell lines tested by immunocytochemistry and Western Blot, respectively. Then we evaluated the effect of recombinant PRL and RPRL antagonist ∆1–9-G129R-hPRL on the chemosensitivity of human GBM cells. While recombinant PRL reduced the cytotoxicity of Cisplatin and Temozolomide, ∆1–9-G129R-hPRL increased the chemosensitivity and reduced the viability and migration of human GBM cells. Our findings suggest that locally synthesized PRL and/or RPRL could constitute therapeutic targets to improve the sensitivity of GBM cells to antineoplastic agents. Thus, we aimed to construct a gene therapy vector encoding ∆1–9-G129R-hPRL to locally inhibit RPRL function in GBM. In order to optimize this gene therapy approach, we assessed the transduction efficiency and toxicity of baculoviral (BV) vs adenoviral (AdV) vectors. We found that both AdVs and BVs efficiently transduce tumors and naïve brain parenchyma in murine orthotopic GBM models. It is important to consider that virtually all patients exhibit preexisting immunity against AdVs, which could impair long term transgene expression. However, BVs are not natural pathogens of humans, therefore, patients lack preexisting immunity against these vectors. Thus, BVs could constitute good candidates for the delivery of ∆1–9-G129R-hPRL in GBM.