Tyrosine Kinase Inhibitors for Glioblastoma Multiforme: Challenges and Opportunities for Drug Delivery

Abstract

Glioblastoma multiforme (GBM) is an aggressive brain tumor with high mortality rates. Due to its invasiveness, heterogeneity, and incomplete resection, the treatment is very challenging. Targeted therapies such as tyrosine kinase inhibitors (TKIs) have great potential for GBM treatment, however, their efficacy is primarily limited by poor brain distribution due to the presence of the blood–brain barrier (BBB). This review focuses on the potential of TKIs in GBM therapy and provides an insight into the reasons behind unsuccessful clinical trials of TKIs in GBM despite the success in treating other cancer types. The main section is dedicated to the use of promising drug delivery strategies for targeted delivery to brain tumors. Use of brain targeted delivery strategies can help enhance the efficacy of TKIs in GBM. Among various drug delivery approaches used to bypass or cross BBB, utilizing nanocarriers is a promising strategy to augment the pharmacokinetic properties of TKIs and overcome their limitations. This is because of their advantages such as the ability to cross BBB, chemical stabilization of drug in circulation, passive or active targeting of tumor, modulation of drug release from the carrier, and the possibility to be delivered via non-invasive intranasal route.

Mechanisms of Resistance and Current Treatment Options for Glioblastoma Multiforme (GBM)

“…Even though good tolerability was reported, therapy with Gefitinib failed for most participants in the first 8-week evaluation of a phase II clinical trial for recurrent GBM [ 152 ]. Previous benefits shown in preclinical studies were also not confirmed in clinical trials with Erlotinib, as monotherapy or in combination [ 38 , 146 ].…”

“…Tyrosine kinase (TK) proteins are a large, multigene family of proteins, whose function is related to the regulation of cell-to-cell signaling. They can be found in cell membranes or in the cytoplasm and are classified as TK receptors or non-receptors, respectively [ 146 ]. TK proteins play important roles in diseases such as cancer and diabetes, mostly due to their function as regulators of cellular processes and homeostasis [ 146 , 147 ].…”

“…They can be found in cell membranes or in the cytoplasm and are classified as TK receptors or non-receptors, respectively [ 146 ]. TK proteins play important roles in diseases such as cancer and diabetes, mostly due to their function as regulators of cellular processes and homeostasis [ 146 , 147 ]. More than 70 tyrosine kinase inhibitors (TKI) have already been approved and successfully used in clinical practice for several tumors, such as metastatic breast cancer, metastatic renal-cell carcinoma, advanced hepatocellular carcinoma, chronic myeloid leukemia, and gastrointestinal stroma tumor [ 148 ].…”

“…Inhibitors of EGFR, such as Osimertinib, Lazertinib, Erlotinib, Gefitinib and Afatinib, have shown potential results for GBM in in vitro and in vivo mouse models. However, clinical outcomes have not been so encouraging [ 146 ]. Even though good tolerability was reported, therapy with Gefitinib failed for most participants in the first 8-week evaluation of a phase II clinical trial for recurrent GBM [ 152 ].…”

“…Imatinib, Dasatinib, Sorafenib, Sunitinib, and Cabozantinib are examples of multi-target TKIs that have been evaluated for GBM [ 38 , 146 , 150 , 151 ], even though, until now, no TKI has been approved for GBM, mostly due to lack of success in clinical trials. This was attributed to their restricted delivery across blood–brain barrier and lack of tumor specificity [ 146 , 151 ].…”