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Current Trends in Glioblastoma Therapies

May 20, 2021 1:00:00 PM / by Champions Oncology

Glioblastoma

Glioblastoma multiforme (GBM) is an aggressive form of primary malignancy of the central nervous system (CNS) that causes brain tumors. GBM has been associated with poor prognoses and high mortality rates and a 5-year relative survival rate ranging from 6-22% percent depending on age of onset[1]. Currently, standard-of-care treatments include cytoreductive surgery followed by chemoradiotherapy, but these are not considered curative treatments, and efficacy varies widely between patients[2]. Temozolomide is a DNA alkylating agent prodrug commonly used for adjuvant chemotherapy in GBM, but treatment resistance is a common occurrence, and this drug is also associated with clinically significantly toxicity[3].

Many preclinical studies and clinical trials have sought to identify targeted therapies that can penetrate the blood-brain barrier and treat GBM. Unfortunately, GBM is a genomically heterogeneous disease and is not characterized by commonly occurring mutations in discrete genes. Attempts at targeted therapies have failed thus far during clinical trials and have included drugs that target the EGFR, PI3K, SRC, and mTOR signaling pathways[4],[5],[6],[7]. Dozens of clinical trials are in progress that target these pathways and may yet identify new therapeutic options that treat GBM[8],.

Glioblastoma brain tumor

Single cell sequencing studies have revealed that GBM carry a wide range of mutations that drive oncogenesis, and mutations typically target common metabolic pathways[9][9]. These divergent drivers of GBM have made radiotherapy an appropriate treatment modality, but resistance occurs frequently and has been linked to intratumoral accumulation of purine metabolites, particularly guanylates. Preclinical studies have indicated that GTP synthesis inhibitors can reverse radiotherapy resistance[10].

Dysregulation in the Wnt signaling pathway has also been observed in GBM[11], and this has been a pivotal finding as Wnt signaling is critical to the development of neural stem cells (NSCs) and drives differentiation, proliferation, and self-renewal in the CNS[12],. Wnt signaling is thought to contribute to formation of GBM stem cells and has also been linked to autophagy-mediated temozolomide resistance[13], thus making Wnt signaling components attractive candidates for targeted therapies. Various Wnt inhibitors are currently being developed or are under investigation as targeted therapies. Other therapies aimed at targeting GBM stem cells are also being explored, as this strategy may overcome failures observed with treatments targeting EGFR, tyrosine kinases and VEGF/VEGFR.

Advances in our understanding of GBM development coupled with improvements of drug deliver to brain tissue will increase the likelihood of identifying effective therapies for GBM. GBM tumors particularly challenging as they are not enriched for immune cells and cannot be treated successfully with adoptive cell therapy or immune checkpoint blockade approaches. Attention is also being focused on better stratifying GBM patients and using molecular characterization to inform treatment decisions. There is great hope that the future of GBM research will lead to effective therapies and improved survival outcomes.

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[1] https://www.cancer.org/cancer/brain-spinal-cord-tumors-adults/detection-diagnosis-staging/survival-rates.html

[2] Lukas RV, Wainwright DA, Ladomersky E, Sachdev S, Sonabend AM, Stupp R. (2019). Newly diagnosed glioblastoma: a review on clinical management. Oncology; 33(3), 91.

[3] Zhang J, Stevens MF, Bradshaw TD. (2012) Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol; 5(1):102-14.

[4] Raizer JJ et al. (2010) A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro. Oncol; 12, 95–103.

[5] Pitz MW et al. (2015). Phase II study of PX-866 in recurrent glioblastoma. Neuro. Oncol; 17, 1270–1274.

[6] Lassman AB et al. (2015). Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627). Neuro Oncol. 17, 992–998.

[7] Chinnaiyan P et al. (2018). A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913. Neuro Oncol. 20, 666–673.

[8] Cruz Da Silva E et al. (2021). A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials. Cancers (Basel);13(8):1795.

[9] Marin-Valencia I et al. (2012). Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab; 15(6):827-37. Erratum in: Cell Metab. 2012 Nov 7;16(5):686.

[10] Zhou W et al. (2020). Purine metabolism regulates DNA repair and therapy resistance in glioblastoma. Nat Comm; 11(1):1-4.

[11] Pulvirenti T et al. (2011). Dishevelled 2 signaling promotes self-renewal and tumorigenicity in human gliomas. Cancer Res; 71(23):7280-90.

[12] Kalani MY et al. (2008). Wnt-mediated self-renewal of neural stem/progenitor cells. Proc Natl Acad Sci U S A; 105(44):16970-5.

[13] Shahcheraghi SH et al. (2020). Wnt/beta-catenin and PI3K/Akt/mTor Signaling Pathways in Glioblastoma: Two main targets for drug design: A Review. Curr Pharm Design; 26(15):1729-41.

Tags: Solid Tumor Oncology