Abstract
Abstract The ability of glioblastoma (GBM) cells to disperse to healthy brain stroma makes it one of the most aggressive and fatal brain cancers. Microglia infiltrate most gliomas and release factors, which favor tumor growth and invasion. Previously we demonstrated that microglia stimulate glioma cell migration/dispersal through the pro-migratory proline rich tyrosine kinase 2 (Pyk2) signaling pathway in glioma cells. The purpose of the present study was to demonstrate that pro-migratory effect of microglia and consequently, glioma cell dispersal into surrounding tumor areas can be significantly reduced by administration of PF-562271, a small molecule Pyk2 inhibitor. Temozolomide (TMZ) is a DNA alkylating agent widely used for GBM patients. TMZ has some inhibitory effect on cell migration, but current treatment with TMZ does not take into account the stimulatory effect of microglia on glioma growth and dispersal. In the present study we investigated combining TMZ with PF-562271 vs. monotherapies with either agent, in relation to glioma cell migration using both in vitro and in vivo approaches. GL261, U87, and A172 glioma cell lines were used for standard invasion and migration assays with and without the presence of microglia. Hematoxillin & Eosin staining of brain sections encompassing the tumor area was used for the measurement of tumor size and invasion distance in GL261 tumor bearing-C57/B6 mice. Our data suggest that PF-562271 (16nM) and TMZ (100µM) reduced in vitro migration of glioma cells in the presence of microglia, but the combination of these drugs had a more prominent effect at a lower concentration (10µM) of TMZ. In vivo experiments demonstrated that oral PF-562271 administration (twice/daily, 25 mg/kg) did not have a significant effect on tumor growth, but reduced invasion of glioma cells at the tumor edge. TMZ (50 mg/kg, once/day, orally) reduced tumor growth, but did not affect invasion at the tumor edge. The combination of TMZ and PF-562271 reduced both tumor growth and invasion of glioma cells. In conclusion these data indicate that TMZ in combination with PF-562271 reduces both tumor growth and tumor dispersal to surrounding areas. Moreover, in vitro experiments revealed a complex effect of these drugs on glioma cell migration, allowing a reduction of the TMZ concentration without the loss of its effect on glioma cell migration. This research was made possible by NIH grant numbers: 1SC2GM102040-01A1, G11 HD052352, G12 RR03035, 8G12MD007583-27, U54 NS039408, Title V PPOHA grant number P031M105050. Citation Format: Kimberleve Rolon-Reyes, Serguey Skatchkov, Misty Eaton, Luis Cubano, Jeffrey Harrison, Lilia Kucheryavykh. PF-562271, a small molecule PYK2 inhibitor, reduces microglial pro-migratory effect and tumor dispersal in C57/B6 glioma bearing model. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A26. doi:10.1158/1538-7445.CHTME14-A26
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