Abstract IA17: Targeting placental growth factor/ neuropilin-1 pathway inhibits growth and spread of medulloblastoma

Abstract Background: Medulloblastoma (MB) is the most common pediatric brain tumor and a heterogeneous disease. Several studies have characterized tumor genetic heterogeneity with the hope of identifying targets for personalized therapy. In fact, inhibitors of Sonic Hedgehog (Shh) - a developmental pathway aberrantly activated in a subset of MBs - are currently being evaluated. Unfortunately, mutations and potential developmental adverse effects in the pediatric population can limit these therapies. We propose targeting the tumor stroma as an efficacious alternative treatment option. In particular, we aim to identify and target crucial cancer cell-stromal cell crosstalk signaling that sustains tumor growth and spread. In this context, we have evaluated the effects of blocking signaling of Placental Growth Factor (PIGF) - a member of the vascular endothelial growth factor (VEGF) family - that is dispensable in development but relevant during disease, in the growth and progression of MB. Here, we show the expression of PIGF and its receptor Neuropilin-1 (NRP-1) across primary tumors; dissect the mechanisms that regulate PIGF secretion and downstream signaling; and demonstrate the dramatic efficacy of specific anti-PIGF and anti-NRP-1 blocking antibodies in three MB models in vivo. Methods: Expression of PIGF and NRP-1 was analyzed in a cohort of 32 surgical samples of pediatric MBs by immunohistochemistry, array-comparative genomic hybridization, and deep-gene sequencing. The correlation between NRP-1 expression and 5-year overall survival was evaluated retrospectively in an independent, clinically annotated cohort of 42 MBs. Human orthotopic xenograft (D283-Med; D341-Med) and spontaneous (Smo/Smo) established tumors were treated with anti-PIGF (Thrombogenics or Genentech) or anti-NRP-1 (Genentech) antibodies. Tumor growth, progression and response to therapy was followed by 1) clinical evaluation of posterior fossa symptoms and body weight; 2) whole-body luminescence and blood GLuc levels; 3) small animal MRI; or 4) Optical Frequency Domain Imaging (OFDI). Results: We report that: 1) PIGF is expressed by more than 90% of primary pediatric MBs, regardless of their genetic subtype or histological classification; and high expression of NRP-1 correlates with poor overall survival of patients; 2) MB cells release Shh ligands that stimulate paracrine production of stromal PIGF by cerebellar granule neurons; 3) PIGF signals through NRP-1 - and independent of vascular endothelial growth factor receptor 1 (VEGFR1) - to activate the Erk/MEK pathway and sustain tumor survival; 4) Blockade of PIGF or NRP-1 with specific antibodies causes dramatic regression of MB, decreases spinal metastatic burden, and prolongs survival in in vivo orthotopic and spontaneous mouse models. Conclusion: This work identifies PIGF as the first common target across MB subgroups and provides insight into the critical role of tumor-stroma interactions. The study demonstrates that targeting PIGF/NRP-1 may provide a safe and efficient treatment option for pediatric MBs and lays the ground for evaluation of anti-PIGF therapy in clinical trials. Reference: M. Snuderl et al, Cell, 152(2):1065-76 (2013). Citation Format: Matija Snurdel, Ana Batista, Nathaniel Kirkpatrick, Carmen Almodovar, Lars Riedemann, Teresa Peterson, Napoleone Ferrara, Michael Klagsbrun, Dan G. Duda, Dai Fukumura, Lei Xu, Peter Carmeliet, Rakesh Jain. Targeting placental growth factor/ neuropilin-1 pathway inhibits growth and spread of medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA17.