New Directions in the Therapy of Glioblastoma

SIMPLE SUMMARY: Despite the continuous development of treatment technology, glioblastoma remains a challenge for modern medicine. The standard of care remains a radical surgical resection combined with adjuvant radiotherapy and chemotherapy with temozolomide. However, the usage of these procedures is not associated with satisfactory treatment responses. Therefore, it is important to develop systemic therapies that support treatment and sometimes represent the only therapeutic option. Molecular targeted therapy and immunotherapy appear to be encouraging approaches. In recent years, a number of key metabolic points for the progression of glioblastoma have been identified. In this review, we presented the therapeutic targets that are currently under study for new clinical trials. The aim of our study was to present and analyze the up-to date literature describing the epidemiology, genetics, and histopathology of glioblastoma, as well as to compare treatment efficacy in patients treated with selected potential antitumor drugs. ABSTRACT: Glioblastoma is the most common histologic type of all gliomas and contributes to 57.3% of all cases. Despite the standard management based on surgical resection and radiotherapy, it is related to poor outcome, with a 5-year relative survival rate below 6.9%. In order to improve the overall outcome for patients, the new therapeutic strategies are needed. Herein, we describe the current state of knowledge on novel targeted therapies in glioblastoma. Based on recent studies, we compared treatment efficacy measured by overall survival and progression-free survival in patients treated with selected potential antitumor drugs. The results of the application of the analyzed inhibitors are highly variable despite the encouraging conclusions of previous preclinical studies. This paper focused on drugs that target major glioblastoma kinases. As far, the results of some BRAF inhibitors are favorable. Vemurafenib demonstrated a long-term efficacy in clinical trials while the combination of dabrafenib and trametinib improves PFS compared with both vemurafenib and dabrafenib alone. There is no evidence that any MEK inhibitor is effective in monotherapy. According to the current state of knowledge, BRAF and MEK inhibition are more advantageous than BRAF inhibitor monotherapy. Moreover, mTOR inhibitors (especially paxalisib) may be considered a particularly important group. Everolimus demonstrated a partial response in a significant proportion of patients when combined with bevacizumab, however its actual role in the treatment is unclear. Neither nintedanib nor pemigatinib were efficient in treatment of GBM. Among the anti-VEGF drugs, bevacizumab monotherapy was a well-tolerated option, significantly associated with anti-GBM activity in patients with recurrent GBM. The efficacy of aflibercept and pazopanib in monotherapy has not been demonstrated. Apatinib has been proven to be effective and tolerable by a single clinical trial, but more research is needed. Lenvatinib is under trial. Finally, promising results from a study with regorafenib may be confirmed by the ongoing randomized AGILE trial. The studies conducted so far have provided a relatively wide range of drugs, which are at least well tolerated and demonstrated some efficacy in the randomized clinical trials. The comprehensive understanding of the molecular biology of gliomas promises to further improve the treatment outcomes of patients.