Abstract 1905: Autophagy inhibitor quinacrine synergistically enhances anti-angiogenic efficacy of Cediranib in intracranial mouse glioma

Abstract

Abstract Despite robust vascularity of malignant gliomas, anti-angiogenic therapy (AAT), largely fails to induce durable responses. We hypothesized that AAT efficacy in treating glioma could be increased by disrupting adaptive mechanisms that enable tumors to survive AAT alone. Hypoxic/nutrient stress conditions, such as those induced by AAT, can activate autophagy in tumor cells, a degradative catabolic pathway that promotes cellular survival during metabolic stress. The anti-malarial agent quinacrine induces late-stage autophagic inhibition, which can induce cell death. We determined whether the angiogenic/anti-tumor efficacy of Cediranib, a VEGF/PDGF receptor tyrosine kinase inhibitor, could be synergistically enhanced through combined administration of quinacrine. A noninvasive, dual bolus perfusion MRI approach was used to assess tumor growth and vascular parameters in the syngeneic 4C8 mouse model of intracranial glioma. Dynamic contrast enhanced (DCE) MRI, provided high resolution maps of Ktrans, an index of vascular permeability. At the same time, dynamic susceptibility contrast (DSC) MRI determined cerebral blood flow (CBF). Once tumor growth was documented by MRI, mice were randomized to untreated (U), Cediranib (C, 6 mg/kg daily), quinacrine (Q, 50mg/kg daily), or Cediranib plus quinacrine (C+Q) groups. Tumor growth rate (days−1, mean±SE) was moderately decreased for C (0.17±0.01) in comparison to U (0.22±0.01) and Q (0.21±0.01) (p<0.05). Tumor growth rate was reduced substantially, with C+Q (0.11±0.004) (p<0.01 versus other groups). Consistent with this, survival (days from tumor growth initiation) was greatly increased for C+Q, 25.3±1.8, versus other groups (p<0.01): 11.0 ± 1.6 (U), 11.5 ± 1.2 (Q), and, 14.3 ± 0.7 (C). Perfusion MRI indicated that mean tumor Ktrans for C (0.13±0.01 min−1) was moderately reduced in comparison to U (0.21±0.04) and Q (0.20±0.2), during the 2nd treatment week (P<0.05). Dramatically reduced Ktrans was observed with C+Q (0.07±0.01; p<0.05 vs U, C, and Q). Consistent with this, mean tumor CBF relative to contralateral brain CBF during the 2nd treatment week, was dramatically lower for C+Q, 1.61±0.06 (p<0.05) compared to other groups: 3.06 ± 0.15 (U), 2.55±0.24 (Q), 3.07±0.47 (C). In vitro MTS cell viability assays of 4C8 glioma cells indicated markedly increased efficacy for combined C+Q under hypoxic conditions: 1μM C/2.5μM Q decreased cell viability by 76±6% and 33±1% with 0.5 and 21% O2, respectively. Combination indices (CI) indicated less than additive effects for C and Q with normal O2, while synergism (CI<1) was observed under hypoxic conditions (CI=0.58, 0.75μM C/1μM Q). In conclusion, the autophagy inhibitor quinacrine synergistically increases the anti-angiogenic/anti-tumor effect of Cediranib in 4C8 mouse glioma. Tumor microenvironment conditions such as hypoxia may play a role in the synergistic interaction. 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 1905. doi:1538-7445.AM2012-1905