Abstract 2481: Exploiting BRAF mutation for therapy of childhood low-grade astrocytoma

Abstract

Abstract Activating mutations of BRAF (predominantly V600E) are common in low-grade astrocytomas (∼23%), and xanthoastrocytomas (60%), with or without loss of the CDKN2A locus. Surgically inoperable astrocytoma has a poor prognosis with greater than half of these patients dying from disease. We have developed two models of low-grade astrocytoma (BT-35, BT-40) by direct heterografting patient tumor into immune-deficient mice. Both tumor lines have multiple copies of BRAF, but only BT-40 has an activating mutation (V600E), and is exquisitely sensitive to the MEK inhibitor AZD6244, whereas BT-35 is intrinsically resistant (Kolb et al. Ped Blood Cancer, 2010). Biochemical characterization showed that MEK1/2 were equally inhibited by AZD6244 treatment in both BT-35 and BT-40 xenografts, as demonstrated by the level and duration of inhibition of phospho-ERK1/2. However, inhibition of MEK1/2 had no effect on TORC1 signaling in BT-35 (insensitive) tumors whereas in BT-40 xenografts TORC1 signaling was completely inhibited by AZD6244. The pathway through which mutant BRAF controls TORC1 signaling is currently under evaluation. However, control of TORC1 by mutant BRAF potentially exposes these cells to therapeutic exploitation. We have shown previously that the TOR kinase inhibitor AZD8055 potently suppresses FANCD2, a protein involved in interstrand cross-link (ICL) repair of DNA damage. Similar to the effect of AZD8055, within 4 days treatment of mice with AZD6244, FANCD2 levels are dramatically reduced and were no longer detected in BT-40 xenografts. Preliminary results show that inhibition of TOR signaling by AZD8055 is synergistic with daily radiation in rhabdomyosarcoma xenografts. We hypothesize that because MEK inhibition leads to suppression of TORC1 signaling and FANCD2 in BT-40 astrocytoma xenografts, that combination of AZD6244 with ionizing radiation or drugs that induce ICL will be selectively synergistic in the context of BRAF mutation. Experiments to test the hypothesis are ongoing. Supported by a Peletonia grant from the Ohio State University. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2481. doi:1538-7445.AM2012-2481