Table 4.

Causes of treatment failure in glioblastoma

Sl.No.	Cause of treatment resistance	Biomarkers	Treatment strategy	Challenges
1	Tumor hypoxia	HIF-1α, HIF-2α	Hyperbaric Oxygen, Allosteric hemoglobin modifiers, hypoxia activated prodrugs & Flurocarbons 8	limited efficacy, side effects including seizures, chemo-radioresistance
2	Telomere dysfunction	TERC, TERT, TA	Telomerase inhibitor (Imetelstat) 9,10	chemo-radioresistance
3	Immunosuppressive GBM microenvironment	CD19, EGFRvIII, HER2, IL-13 Rα2	Car T-cell therapy 11	Immunosuppressive effects of RT, TMZ and corticosteroids
		CTLA4, PDL1, PD1	Blockade checpoint inhibitors (Ex: PD1 checkpoint blockade), Vaccines, Adoptive cell transfer, Oncolytic viruses 12
	Tumor heterogeneity	EGFRvIII, SOX2, Olig2, MET, PDGFRA	Targeted therapy 13	Identify and target all clonal sub-populations
4	Tumor microtubules	Cx43, GAP-43, STMN1	Anti-microtubule activity drugs 14	Development of drug resistance
5	Inherent radioresistance	MGMT promoter methylation	Radiosensitizers (Ex: TMZ)	Unmethylated MGMT in GBM
6	Conventional fraction in RT	HIF-1α	Altered fractionation, Simultaneous integrated boost-RT	Microvascular damage, decreased vascular endothelial apoptosis 15

IL-13 Rα2: Interleukin-13 Receptor alpha 2; CTLA4: Cytotoxic T-Lymphocyte Associated Protein 4; PDL1: Programmed cell death ligand 1; PD1: Programmed cell death protein-1; Sox2: (sex determining region Y)-box 2; Olig2: Oligodendrocyte Transcription Factor 2; MET: MET Proto-Oncogene; PDGFRA: Platelet Derived Growth Factor Receptor Alpha; Cx43: Connexin 43; GAP-43: Gap associated protein 43; STMN1: Stathmin 1