Alterations of the tumor microenvironment (TME) in recurrent glioblastoma following apatinib in combination with temozolomide.

Abstract

e14018 Background: Glioblastoma (GBM) is the highly malignant primary central nervous system tumor. The standard treatment for glioblastoma is maximal surgical resection followed by concomitant radiotherapy and temozolomide chemotherapy, but patient’s survival still remains poor. At present, apatinib in combination with temozolomide (TMZ) has achieved reasonable clinical efficacy in the treatment of recurrent glioblastoma (rGBM), however, there are currently no clear biomarkers related to clinical efficacy or prognosis. Methods: This retrospective study was enrolled 22 rGBMs treated with apatinib in combination with TMZ and 6 patients who received standard radiotherapy combined with TMZ and experienced recurrence. At the same time, we collected their tissue samples for RNA transcriptome analysis by the Nanostring nCounter platform. In prognosis analysis, long survival benefit is defined as a PFS≥4.2 months, and short survival benefit is defined as a PFS<4.2 months. This PFS threshold was primarily referenced from a Phase III study of bevacizumab combined with chemotherapy for rGBM. The study was approved by the institutional ethics committee of Sanbo Brain Hospital, Capital Medical University (SBNK-YJ-2021-010-02) and informed consent was also obtained from the patients. Results: The differential gene of pre and post standard chemoradiotherapy results suggest that standard treatment has reduced the expression of genes associated with tumor proliferation and up-regulated the expression of the genes associated with the immune response in rGBM. In apatinib combined TMZ patients, compared to the non-response group, the response group had significantly up-regulated expression of genes related to endothelial cells and apoptosis. Enrichment analysis revealed that signaling pathways related to cell proliferation were down-regulated in the response group. In terms of prognosis, compared with the short-survival benefit group (< 4.2 months), four tumor progression-associated genes were down-regulated in response group (≥4.2 months). Hypoxia related-genes was significantly up-regulated in the long survival benefit group. Enrichment analysis showed that genes related to cell proliferation were also down-regulated in the long-survival benefit group, while the expression of signaling pathway genes related to cell activation, and immune response was significantly up-regulated. Conclusions: Our study suggests that the combination of apatinib and TMZ may potentially provide clinical benefits in treating rGBM by modulating genes associated with cell proliferation, promoting apoptosis, regulating hypoxia, and enhancing immune response within the tumor microenvironment. Clinical trial information: NCT04814329 .