Prolactin and its receptor as therapeutic targets in Glioblastoma

ASAD AS; NICOLA CANDIA AJ; ABT A; ROMANOWSKI V; PISERA DA; SAGRIPANTI S; ORRILLO SJ; PIDRE ML; SEILICOVICH A; CANDOLFI M; GONZALEZ N; ZUCCATO CF; ZANETTI FA; GOFFIN V; FERRARIS J

New Orleans

Congreso; 23rd Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology; 2018

Society for Neuro-Oncology

Prolactin (PRL) has been detected in glioblastoma (GBM) biopsies and many GBMpatients exhibit hyperprolactinemia, which has a positive correlation with theproliferation index and the vascular density of brain tumors. Although PRL has beenassociated with the development of hormone-dependent tumors, its role in thepathogenesis of GBM remains unknown. Our meta-analysis of transcriptomic data fromthe Cancer Genome Atlas revealed that PRL is expressed in 12% of low grade gliomas(LLG, 65/530) and 28% of GBM (45/150) biopsies, while its receptor (RPRL) is presentin virtually all LLG and GBM samples. We detected expression of PRL and RPRL in allhuman and murine GBM cell lines tested by immunocytochemistry and Western Blot,respectively. We next evaluated the effect of recombinant PRL and RPRL antagonist∆1?9-G129R-hPRL on the chemosensitivity of human GBM cells. While recombinantPRL reduced the cytotoxicity of Cisplatin and Temozolomide, ∆1?9-G129R-hPRLincreased the chemosensitivity and reduced the viability and migration of human GBMcells. Our findings suggest that locally synthesized PRL and/or RPRL could constitutetherapeutic 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 tolocally 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(Ad) vectors. We found that both Ads and BVs efficiently transduce tumors and naïvebrain parenchyma in murine orthotopic GBM models. It is important to consider thatvirtually all patients exhibit preexisting immunity against Ads, which could impair longterm transgene expression. However, BVs are not natural pathogens of humans,therefore, patients lack preexisting immunity against these vectors. Thus, BVs couldconstitute good candidates for the delivery of ∆1?9-G129R-hPRL in GBM.