Novel drug target identified for glioblastoma treatment

Written by Peter Brown, Future Science Group

A group of researchers led by Masaharu Noda and Akihiro Fujikawa of the National Institute for Basic Biology (Okazaki, Japan) have recently demonstrated that the pharmacological inhibition of R5 receptor-type protein tyrosine phosphatases (RPTPs) by a small molecule, termed NAZ2329, could be a promising strategy for the treatment of malignant gliomas.
Glioblastoma is the most malignant brain tumor with high mortality. Cancer stem cells are thought to be crucial for tumor initiation and its recurrence after standard therapy with radiation and temozolomide chemotherapy.

The R5 subfamily of RPTPs comprises protein tyrosine phosphatase receptor type Z (PTPRZ) and protein tyrosine phosphatase receptor type G (PTPRG). A previous study indicated an association between human PTPRZ expression and cancer stemness. However, the functional roles of PTPRZ activity in glioma stem cells have remained unclear.

In the investigation, the team observed that PTPRZ knockdown strongly inhibited tumor growth of C6 glioblastoma cells in murine xenograft models. Suppressive effects on the cancer stem-like properties of the cells were also observed following the knockdown of PTPRG.

Additionally, the team identified that NAZ2329, a cell-permeable small molecule, allosterically inhibits both PTPRZ and PTPRG.

NAZ2329 efficiently suppressed stem cell-like properties of glioblastoma cells in culture and the co-treatment of NAZ2329 with temozolomide, an alkylating agent, significantly slowed tumor growth in C6 glioblastoma xenograft murine models. These results indicate that pharmacological inhibition of R5 RPTPs is a promising strategy for the treatment of malignant gliomas.

Sources: Fujikawa A, Sugawara H, Tanaka T et alTargeting PTPRZ inhibits stem cell-like properties and tumorigenicity in glioblastoma cellsSci. Rep. 7, 5609 (2017);