Abstract B202: Combined therapy of temozolomide and PF-562271, a PYK2 inhibitor, reduces glioma tumor growth and dispersal compare to temozolomide monotherapy

Abstract

Abstract Microglia infiltrate majority of gliomas and release factors, which favor tumor growth and dispersal. Previously we demonstrated that microglia residing within the tumor stimulate glioma cell dispersal through the proline rich tyrosine kinase 2 (Pyk2) signaling cascade (Rolon-Reyes et al. 2015). We hypothesize that the use of pharmacological inhibitors of Pyk2 in applied therapy can significantly reduce the dispersal of tumor cells and improve the outcome of treatment. In the present study, we investigated both in vitro and in vivo, the effect of the combined treatment of glioblastoma with temozolomide (TMZ) together with PF-562271 (a Pyk2 and FAK inhibitor), vs. TMZ monotherapy. Proliferation and migration assays were performed for a number of primary human glioma cell lines, as well as U87 and HS683cell lines in the presence and absence of microglia. Tumor size and invasion area were evaluated in brains of GL261 tumor bearing C57BL/6 mice for the assessment of the effectiveness of treatment. Our data demonstrate that PF-562271 (16nM) and TMZ (100μM) given alone reduced in vitro migration and proliferation of glioma cells in the presence of microglia. PF-562271 (16nM) given in combination with TMZ at a concentration of just 10μM provided the same effect as TMZ 100 μM along, without reduction of efficacy. In vivo experiments demonstrated that oral administration of PF-562271 (twice/daily, 25 mg/kg, orally) reduced invasion of glioma cells at the tumor edge, while TMZ (50 mg/kg, once/day, orally) reduced the tumor growth. Combined treatment revealed significantly more prominent effect on both tumor growth and invasion compare to monotherapy. These data indicate that the combination of TMZ and PF-562271 reduces both tumor growth and dispersal of tumor cells to surrounding areas. Moreover, in vitro experiments revealed a complex effect of these drugs on glioma cell proliferation and migration, allowing the reduction of the applied concentration of TMZ without the loss of its therapeutic effect. This research was made possible by NIH grant numbers: 1SC2GM102040-01A1, 8G12MD007583-27, Title V PPOHA grant number P031M105050, NIH NIMH R25 MH055929 and RO1-CA18382701A1. Citation Format: Kimberleve Rolon-Reyes, Luis A. Cubano, Alfredo Quiñones-Hinojosa, Lilia Kucheryavykh. Combined therapy of temozolomide and PF-562271, a PYK2 inhibitor, reduces glioma tumor growth and dispersal compare to temozolomide monotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B202.