Targeting Heat Shock Proteins in Malignant Brain Tumors: From Basic Research to Clinical Trials
Aisha Babi1, Karashash Menlibayeva1, Torekhan Bex1
1National Centre for Neurosurgery, Turan Ave., 34/1, Astana 010000, Kazakhstan.
Abstract:
Heat shock proteins (HSPs) are conservative and ubiquitous proteins that are expressed both in prokaryotic and eukaryotic organisms and play an important role in cellular homeostasis, including the regulation of proteostasis, apoptosis, autophagy, maintenance of signal pathways, protection from various stresses (e.g., hypoxia, ionizing radiation, etc.). Therefore, HSPs are highly expressed in tumor cells, including malignant brain tumors, where they also associate with cancer cell invasion, metastasis, and resistance to radiochemotherapy. In the current review, we aimed to assess the diagnostic and prognostic values of HSPs expression in CNS malignancies as well as the novel treatment approaches to modulate the chaperone levels through the application of inhibitors (as monotherapy or in combination with other treatment modalities). Indeed, for several proteins (i.e., HSP10, HSPB1, DNAJC10, HSPA7, HSP90), a direct correlation between the protein level expression and poor overall survival prognosis for patients was demonstrated that provides a possibility to employ them as prognostic markers in neuro-oncology. Although small molecular inhibitors for HSPs, particularly for HSP27, HSP70, and HSP90 families, were studied in various solid and hematological malignancies demonstrating therapeutic potential, still their potential was not yet fully explored in CNS tumors. Some newly synthesized agents (e.g., HSP40/DNAJ inhibitors) have not yet been evaluated in GBM. Nevertheless, reported preclinical studies provide evidence and rationale for the application of HSPs inhibitors for targeting brain tumors.
Insights
Heat shock proteins (HSPs) are crucial for cell stability and are elevated in brain tumors, correlating with poor prognosis. Targeting HSPs with inhibitors shows promise for treating central nervous system malignancies.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Heat shock proteins (HSPs) are vital for cellular homeostasis and are overexpressed in cancer cells, including brain tumors.
- HSP expression is linked to tumor progression, invasion, metastasis, and resistance to therapy in central nervous system (CNS) malignancies.
Purpose of the Study:
- To review the diagnostic and prognostic significance of HSP expression in CNS malignancies.
- To explore novel therapeutic strategies targeting HSPs in brain tumors.
Main Methods:
- Literature review of studies on HSP expression in CNS tumors.
- Analysis of diagnostic and prognostic values of specific HSPs (e.g., HSP10, HSPB1, DNAJC10, HSPA7, HSP90).
- Evaluation of HSP inhibitors as monotherapy or in combination treatments.
Main Results:
- Elevated levels of HSP10, HSPB1, DNAJC10, HSPA7, and HSP90 correlate with poorer patient survival, suggesting their use as prognostic markers.
- HSP inhibitors (targeting HSP27, HSP70, HSP90) show therapeutic potential in various cancers, but their application in CNS tumors is underexplored.
- Preclinical data support the rationale for using HSP inhibitors against brain tumors, with some agents like HSP40/DNAJ inhibitors yet to be evaluated in glioblastoma (GBM).
Conclusions:
- HSP expression serves as a potential prognostic biomarker in neuro-oncology.
- Targeting HSPs with inhibitors represents a promising therapeutic avenue for CNS malignancies, warranting further investigation.
- Further research into HSP inhibitors, including novel agents, is crucial for developing effective brain tumor treatments.
