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Microbes & Immunity Glioblastoma therapy: Immunotherapy and inhibitors

In summary, the core challenge in drug discovery and For instance, dacomitinib, an irreversible EGFR TKI
therapeutic intervention for GBMs can be regarded as a frequently used for the treatment of non-small-cell lung
paradox: physiological processes and anatomical structures carcinoma, has shown substantial efficacy in inhibiting
that are highly adaptive and neuroprotective in a healthy intracranial tumorigenicity, tumor cell proliferation, and
brain microenvironment are transformed into the most increased tumor cell apoptosis in GBM xenografted mice.
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vital source of supply and nourishment for the tumor cells, Lapatinib, a dual- and multi-targeting kinase inhibitor,
enhancing their survival and further perpetuating their binds to the ATP pocket of EGFR/HER2 and prevents
aggressive and infiltrative nature. tyrosine kinase phosphorylation, leading to the inhibition
of GBM cell growth signaling pathways: mitogen-activated
6.2. Advances protein kinase (MAPK) and phosphatidylinositol 3-kinase/
Despite significant challenges to the effective drug protein kinase B (PI3K/AKT). Moreover, the inhibition
delivery in GBM, there are substantial ongoing preclinical of MAPK and PI3K/AKT, the major growth signaling
and clinical explorations into the therapeutic potential pathways overexpressed in GBM cells, directly leads to the
of SMIs, dual- and multi-targeting kinase inhibitors, inhibition of GBM tumorigenicity and eventual GBM cell
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EGFR, and fibroblast growth factor receptor inhibitors. death. Despite its efficacy, lapatinib treatment induces
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Historically, advances in the development of SMIs for cytotoxic and genotoxic effects. To counteract lapatinib-
treating GBM were limited by their low permeability induced cytotoxicity, patients receive a combination therapy
across the BBB, despite their high selectivity and efficacy. of lapatinib and sorafenib: a selective multi-kinase inhibitor
However, contemporary advances in medicinal chemistry known to downregulate expression of myeloid cell leukemia
have allowed for the assembly of SMIs with diverse 1, a known driver of lapatinib resistance. 94-96 The combination
lipophilic structural components that can target small- therapy stated above is of profound significance in the
molecular target mediators responsible for the regulation therapeutic potential of SMIs as anti-GBM drugs due to
of known signaling pathways characteristic of GBM their high permeability across the BBB, substantial efficacy
tumorigenicity. 90-92 Hence, there is a renewed emphasis on and selectivity, and low cellular and genetic toxicity.
developing anti-GBM SMIs with optimal pharmacokinetic An indispensable feature of effective SMI as an anti-
properties that effectively permeate the BBB/blood-brain GBM drug is the ability to permeate both the BBB and
tumor barrier (BBTB), along with minimal drug resistance BBTB. The SMIs must have sufficient lipophilic properties
and cytotoxicity. in order for them to pass through the BBB/BBTB. Hence, the

Table 3. A detailed summary of small‑molecule inhibitors in glioblastoma therapy

SMI Mechanism of action
Dacomitinib Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. By covalently binding to the
ATP-binding site of EGFR, dacomitinib inhibits downstream proliferative signaling, including MAPK and PI3K/AKT
pathways, inducing tumor cell apoptosis. Preclinical studies have shown efficacy in crossing the BBB and targeting
EGFR-mutant glioblastoma models.
Lapatinib Lapatinib is a dual EGFR/HER2 tyrosine kinase inhibitor that binds to the ATP pocket of both receptors, thereby
halting downstream oncogenic signaling. Lapatinib also modulates the PI3K/AKT and MAPK pathways, critical
for glioblastoma cell proliferation and survival. Its combination with sorafenib has shown promise in overcoming
resistance mediated by Mcl-1.
FGFR and multitarget Novel SMIs such as pemigatinib (FGFR inhibitor) and multitarget kinase inhibitors inhibit critical growth and
inhibitors survival pathways in GBM cells. These agents hold promise due to their ability to simultaneously target multiple
oncogenic pathways, thereby reducing the risk of therapeutic resistance.
Sorafenib Sorafenib is a multikinase inhibitor targeting VEGFR, PDGFR, and RAF kinases. It has been used in combination
with other TKIs to counteract resistance mechanisms and inhibit angiogenesis, a hallmark of GBM progression.
Sorafenib’s ability to modulate both tumor cell proliferation and the tumor microenvironment underscores its
potential as a dual-action therapy.
Nitrogen-enriched SMIs Alkylamine-based SMIs, including piperazine and morpholine derivatives, exhibit enhanced BBB permeability due
to their lipophilic properties. By modulating the oil-water partition coefficient, these compounds improve central
nervous system bioavailability and selectively inhibit signaling pathways implicated in GBM progression.
Abbreviations: BBB: Blood-brain barrier; EGFR: Epidermal growth factor receptor; FGFR: Fibroblast growth factor receptor; GBM: Glioblastoma
multiforme; HER2: Human epidermal growth factor receptor 2; MAPK: Mitogen-activated protein kinase; Mcl-1: Myeloid cell leukemia 1;
PDGFR: Platelet-derived growth factor receptor; PI3K/AKT: Phosphatidylinositol 3-kinase/protein kinase B; RAF: Rapidly accelerated fibrosarcoma;
SMIs: Small-molecule inhibitors; TKIs: Tyrosine kinase inhibitors; VEGFR: Vascular endothelial growth factor receptor.

Volume 2 Issue 4 (2025) 137 doi: 10.36922/mi.5075