Heat shock proteins (HSPs) also known as stress proteins are an important class of proteins that are activated by the cells in response to heat shock or in response to stimuli (external or internal) such as unavailability of nutrition, heat, and cold, hypoxia and so on(Bond and Schlesinger, 1987). These classes of proteins are involved in the presentation of antigens, assembly of hormonal receptors, protein folding, and cell trafficking(Lianos et al., 2015). Due to the various roles that HSPs play in maintaining cellular integrity, a disruption in their machinery causes a depletion in cellular proteostasis leading to cell death(Saibil, 2013). Due to this malfunction, their levels are significantly increased in cancerous cells as compared to the normal tissue(Hu et al., 2022). Therefore, their mechanism is taken up by the malignant cells for their proliferation and survival(Sherman et al., 2007). As HSPs play an intricate role in the origin of these cancerous cells, increased cellular growth and the maintenance of tumor cells show their importance in cancer biology and therefore, can be employed as potential therapeutic targets. HSPs also play an important role in cancer cell evasion, tumor cellular division, mechanism of DNA repair, metastasis, and invasion into the surrounding normal cells(Hasan et al., 2022). These HSPs are classified based on the molecular weights comprising different families- HSP90, HSP110, DNAJ, and smaller HSPs(Kampinga et al., 2009).

Malignant tumors that originate from the brain are hard to treat due to their location of origin as they are deeply embedded within the brain, their ability to metastasize rapidly, and aggressive behavior thereby, leading to poor prognosis in patients and decreased overall survival. Glioblastomas (GBMs) and ependymomas are Grade IV tumors that originate from the glial cells and are the most aggressive tumors of the central nervous system (CNS)(Han et al., 2018). Ependymomas are tumors of the neuroectodermal region(Oppenheim et al., 1994) and arise from the glial cells and are present in the parenchyma of the brain due to the migration of the ependymal cells of the fetus from the periventricular areas(Centeno et al., 1986). The prevalence of ependymoma is higher in males as compared to females and can happen in age groups(De Angelis et al., 2013). Overall survival of the patients suffering from ependymoma remains around 40%(Gatta et al., 2002). Glioblastoma on the other hand is the most commonly occurring brain tumor and can arise from oligodendrocytes, astrocytes, or ependymal cells. Their classification is based on the site of the origin and can be defined as either oligodendrogliomas, astrocytomas, or glioblastomas(Masui et al., 2016). These tumors are more aggressive than ependymomas are more lethal and account for almost 75% of the cases recognized by the World Health Organization (WHO)(Komori, 2022.). Standard therapy in glioblastoma remains temozolomide followed by radiotherapy, which causes short survival and poor prognosis in patients. The median survival in patients suffering from glioblastoma remains only 10–16 months after treatment(Krex et al., 2007). In both the tumors described there is a lack in therapeutically targeting these tumors as these tumors have unpredictable etiologies and the complex mechanism of these tumors is still unknown. The availability of information regarding the role of chemotherapy in the case of ependymoma(Bouffet and Foreman, 1999) is very limited, and only surgery remains an option. Although the potency to counter the primary tumors in both the high-grade and low-grade ependymomas is not upon the mark more aggressive therapies are being employed in the clinics to find some better therapeutics in countering ependymomas. Here HSPs come into counterplay as they mediate several cellular processes and could be a potential therapeutic avenue in countering both GBMs and ependymomas.

HSP90 is the most studied class and its inhibitors are found to be effective in the treatment of cancer. One study investigated the role of 17-allylamino-17demethoxygeldanamycin (17-AAG) or Tanespimycin as a therapeutic agent in GBM(Sauvageot et al., 2009). This inhibitor was found to be effective in combination with Olaparib and also caused the inhibition of Poly ADP-ribose polymerase (PARP) in the case of glioblastoma. However, no study claims its role in the inhibition of ependymomas. Another study used ZD1839 (Iressa), which is an inhibitor of epidermal growth factor receptor (EGFR) against glioma cells(Premkumar et al., 2006). Inhibitors of HSP70 such as VER-155008, and MAL3–101 also showed promising results against various brain tumors(Braunstein et al., 2011). Studies have also shown that cannabinoid agonist such as WIN55–212-2 was found to be efficient in human glioblastoma cell line U-251MG and also showed to alter the expressional levels of HSP70, cathepsin, and p53(Silva et al., 2019). These studies suggest that targeting HSPs can be more fruitful and hence, more studies are needed to be done against HSPs to understand the role of HSPs in countering both tumors. Therefore, our findings may provide a better understanding of the pathways of the HSPs that are mutually dysregulated in both GBMs and ependymomas, and this opens new opportunities in the therapeutic options in both brain malignancies.