EXTH-12. REPURPOSING PROPRANOLOL AS AN ANTI-TUMOR AGENT FOR VON HIPPEL-LINDAU DISEASE

von Hippel-Lindau disease (VHL) is a tumor predisposition syndrome characterized by the development of CNS hemangioblastomas (VHL-HB) and renal cell carcinomas (RCC) due to hypoxia inducible factor activation. Due to a lack of effective medical therapies for VHL, HBs/RCCs may lead to significant morbidity and mortality, ultimately necessitating numerous neurologic and renal surgeries. Propranolol is an FDA approved beta-1/2 antagonist discovered to harbor anti-tumor effects for infantile hemangiomas (IH), and possibly VHL-HBs. We investigated whether propranolol has anti-tumor activity against VHL-related HBs/RCCs. Patient-derived VHL-HBs or 786-0-VHL-/- RCC cells were treated with clinically relevant concentrations of propranolol in-vitro and assessed with viability assays, flow cytometry, QT-PCR and western blots. In-vivo confirmation of propranolol anti-tumor activity was confirmed in athymic nude mice bearing 786-0 xenograft tumors. Lastly, patients enrolled in a VHL natural history study (NCT00005902) who were also on propranolol were identified. Propranolol activity against VHL-HBs was assessed retrospectively with volumetric HB growth kinetic analysis. Propranolol decreased HB and RCC viability in-vitro with an IC50 of 100µM and 200µM, respectively. Similar to prior reports in IH, propranolol induced apoptosis and led to increased VEGF-A mRNA expression in patient-derived VHL-HBs and 786-0 cells. Intracellular VEGF protein levels were not affected by propranolol. Tumor bearing nude mice exposed to propranolol had slower tumor progression compared to controls (33% volume reduction at 7 days, p < 0.005). Four patients harboring 76 CNS-HBs started propranolol therapy during a longitudinal VHL-HB study. HBs in these patients tended to grow slower (m=0.19 versus 0.13, p=0.4) during propranolol treatment. Propranolol decreases VHL-HB/RCC viability in-vitro likely by apoptosis and modulation of VEGF expression. Propranolol abrogates 786-0 xenograft tumor progression in-vivo and retrospective clinical data suggests that propranolol curtails HB growth. These results suggest propranolol may play a role in treatment of VHL-related tumors.