Glioblastoma is an extraordinarily aggressive type of brain cancer due to its invasive and proliferative nature. The tumor microenvironment, with microglia as a critical player, has an important role in tumor progression. Microglia infiltrate majority of gliomas and release factors, which favor tumor growth and invasion. Previously we demonstrated that microglia residing within the tumor stimulate glioma cell invasion through the proline rich tyrosine kinase 2 (Pyk2) signaling cascade. We hypothesize that the use of pharmacological inhibitors of Pyk2 together with currently applied chemotherapy can significantly reduce invasiveness of glioblastoma tumor and improve the outcome of the treatment. Using C57Bl/6-Gl261 mouse glioma implantation model we investigated the effect of the combined treatment for glioblastoma with temozolomide (TMZ, 50 mg/kg, once/day, orally) together with a Pyk2 inhibitor PF562271 (twice/daily, 25 mg/kg, orally) vs. TMZ monotherapy. Treatment was provided during 14 days, beginning the 5th day after glioma implantation. For the assessment of the effectiveness of treatment animals’ survival, tumor size, and invasion area were evaluated. Western blot were used for the evaluation of the level of Pyk2 phosphorylation in tumor cells. For the purification of glioma cells from total tumor tissue Percol gradients were used. The study revealed that treatment with PF562271 reduced invasion of glioma cells at the tumor edge, while TMZ reduced the tumor growth. Combined treatment showed significantly more prominent effect on reduction of tumors growth compared to TMZ monotherapy and additionally reduced invasiveness of tumors similar to PF562271 monotherapy. In both PF562271 monotherapy and combined treatments the downregulation of Pyk2 phosphorylation in glioma cells has been recorded. Survival analysis demonstrated a significance increase of survival of animals received combined treatment compare to TMZ monotherapy. In conclusion, we can state that combined treatment with TMZ together with PF562271 reduced Pyk2-related tumor growth and invasiveness and increased animal survival. This research was made possible by NIH grant numbers: 1SC2GM102040, G12MD007583, R25GM110513, Puerto Rico Science, Technology, and Research Trust grant number 2016-00157, and US Department of Education Grant number P031S130068.

Citation Format: Jescelica Ortiz-Rivera, Kimberleve Rolón-Reyes, Alejandro Albors, Luis Cubano, Lilia Kucheryavykh. PF562271, a Pyk2 inhibitor, reduces glioma tumor growth and invasion in C57Bl6-Gl261 mouse glioma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1092. doi:10.1158/1538-7445.AM2017-1092

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.