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Koehler, A. Molecules for Glioblastoma Therapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/7307 (accessed on 15 April 2024).
Koehler A. Molecules for Glioblastoma Therapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/7307. Accessed April 15, 2024.
Koehler, Abigail. "Molecules for Glioblastoma Therapy" Encyclopedia, https://encyclopedia.pub/entry/7307 (accessed April 15, 2024).
Koehler, A. (2021, February 16). Molecules for Glioblastoma Therapy. In Encyclopedia. https://encyclopedia.pub/entry/7307
Koehler, Abigail. "Molecules for Glioblastoma Therapy." Encyclopedia. Web. 16 February, 2021.
Molecules for Glioblastoma Therapy
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Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor. The current standard of care for GBM is the Stupp protocol which includes surgical resection, followed by radiotherapy concomitant with the DNA alkylator temozolomide; however, survival under this treatment regimen is an abysmal 12–18 months. New and emerging treatments include the application of a physical device, non-invasive ‘tumor treating fields’ (TTFs), including its concomitant use with standard of care; and varied vaccines and immunotherapeutics being trialed. Some of these approaches have extended life by a few months over standard of care, but in some cases are only available for a minority of GBM patients. Extensive activity is also underway to repurpose and reposition therapeutics for GBM, either alone or in combination with the standard of care. 

glioblastoma brain cancer

1. Molecular Classification

Glial tumors can be divided into two categories: diffuse and circumscribed [1]. Diffuse tumors are highly likely to recur due to their nature of malignancy by infiltrating surrounding brain tissue, as opposed to the benign growth pattern of circumscribed tumors. Diffuse gliomas can further be categorized as WHO grades II, III, or IV tumors. Glioblastoma multiforme (GBM) is synonymous with a WHO grade IV malignancy and accounts for more than half of all adult primary brain tumors [1][2]. In adult populations, primary tumors are typically more likely to affect elderly patients, whereas secondary tumors typically affect patients 45 years of age or younger [2][3]. GBMs can be primary tumors, signifying they are grade IV at baseline or secondary tumors that have evolved from lower grade tumors. Low grade histology divisions include astrocytoma, oligodendroglioma, oligoastrocytoma, and the three aforementioned anaplastic forms [1][3]. The four major genetic and epigenetic irregularities noted in GBM are derived from mutations in the metabolic enzyme isocitrate dehydrogenase 1 and 2 genes (IDH1/2), amplification in the epidermal growth factor receptor (EGFR), amplification of platelet derived growth factor alpha (PDGFRA), and the loss or mutation of neurofibromatosis type 1 gene (NF1) [1][3][4][5]. Primary tumors often show a high level of gene expression or mutation in oncoproteins such as EGFR or NF1 loss or mutation, while secondary GBMs typically express mutations in IDH1/2 [1][3][4][5]. IDH wild type is most consistent in GBM primary tumors, whereas IDH mutant is consistent with low-grade gliomas and secondary GBM [4]. GBMs can be further divided into four subtypes based on genomic abnormalities. These four subtypes are proneural, neural, classical, and mesenchymal. Previous studies have shown that mesenchymal subtypes have lower NF1 expression, but more specifically, focal hemizygous deletions of a region at 17q11.2 which contains the gene NF1 [5]. Proneural subtypes are often associated with younger age patients [3]. They express alterations in the PDGFRA gene with either higher amplification of the locus at 4q12 or multiple point mutations, and they also express point mutations in IDH1 [5]. Higher levels of PDGFRA amplifications are most often seen in pediatric GBMs, although childhood GBM is less common [1]. The neural subtype is classified by expression of neuron markers including NEFL, GABRA1, SYT1, and SLC12A5 [5]. Neuron projection and axon and synaptic transmission are gene ontologies associated with this subtype [5]. The classical subtype is commonly characterized by EGFR amplification or mutation [5]. Knowledge of the genetic discrepancies, tumor origination, histology, and DNA methylation patterns allow for more precise identification of tumors which predicts patient prognosis and guides possible treatment options.

2. Cellular Pathways in GBMs

GBMs rely heavily on different cellular pathways for growth, signaling, proliferation, and migration, among other things. The receptor tyrosine kinase (RTK) pathway is a major pathway in which GBM malignancies capitalize. Receptors include EGFR, vascular endothelial growth factor receptor (VEGFR), PDGFR, hepatocyte growth factor receptor (HGFR/c-MET), fibroblast growth factor receptor (FGFR), and insulin-like growth factor 1 receptor (IGF-1R) [6]. When these receptors are bound with a ligand, they trigger two RTK pathways: Ras/MAPK/ERK and PI3K/ATK/mTORC [6]. In the Ras/MAPK/ERK pathway, the Ras protein is activated through phosphorylation of GDP to GTP [6]. Ras activation leads to MAP kinase activation which then activates ERK through phosphorylation [6]. Activation of this pathway promotes tumorigenesis, cell proliferation, cell migration, and angiogenesis through increased VEGF expression [6]. The PI3K/ATK/mTORC pathway is activated by transmembrane tyrosine kinase growth factor receptors and integrins, and G-protein-coupled receptors [6]. A series of events occur to activate ATK, mTORC, and S6K1 [6]. PTEN works to counteract the activation of PI3K signaling by dephosphorylating PIP1 and PIP2, which are directly responsible for activating ATK [6]. This pathway is also responsible for inhibiting p53 and IKB, which are known for anti-tumor progression [6]. The PI3K/ATK/mTORC pathway leads to GBM cell survival, growth, proliferation, and even angiogenesis due to increased VEGF expression [6]. This pathway is found to be altered in nearly 86–90% of GBM cases studied in a recent review [6].

3. Current Treatment Options

Despite advances in molecular studies and multimodal treatment approaches, the prognosis of GBM patients remains dismal [7][8][9][10][11][12][7], with a median survival of ~14 months [8]. Therefore, there is a critical demand for new, life-extending approaches. Upon diagnosis, GBM patients typically follow the current standard of care, known as the Stupp protocol, undergoing maximal safe tumor resection. This is most often followed by adjuvant radiation and chemotherapy. Temozolomide, a DNA alkylating agent approved more than two decades ago, remains the primary chemotherapeutic for newly diagnosed GBMs [9]. Unfortunately, recurrence is observed in almost all patients, with limited therapeutic options available thereafter [7][10]. Most often recurrent GBM patients receive bevacizumab (brand name: Avastin®), a monoclonal antibody, for palliative support. Other options for the newly diagnosed and recurrent treatment include application of an FDA approved physical device, non-invasive alternating electric field therapy or ‘tumor treating fields’ (TTFs), including its concomitant use with standard of care. TTFs, administered through use of the Optune® device, are most commonly applied to supplement treatment therapies to halt tumor growth [11]. Vaccines and immunotherapy have shown a degree of effectiveness for prostate cancer and melanoma, albeit responses are not durable [12]. Trials are ongoing with both approaches for a subset of qualifying GBM patients. Vaccines offer a boost to a patient’s immune system, which may prompt a response to tumor antigens [12]. The intent is that vaccinations, following the completion of the standard of care, will initiate an immune response for tumor antigens in the event of recurrence.

4. Barriers to Identifying Effective Treatment

Barriers to the development of new therapeutic agents for GBMs include: (1) lack of selective, novel “druggable” targets; (2) inability of most drugs to cross the blood-brain barrier (BBB), penetrate the brain-tumor barrier (BTB), and selectively accumulate in tumor cells [13]; (3) molecular heterogeneity of GBMs [14]. Regarding the BBB/BTB, dysfunctional BBB/BTB as well as abnormal blood vessels, stem from hypoxic environments caused by metabolic demands of gliomas which increase angiogenesis and VEGF expression [11]. Abnormal blood vessels allow oxygen and nutrient delivery to the tumor and enable cell migration [15]. It is also important to note that the majority of patients undergoing treatment for GBMs develop resistance to standard of care therapy [13].

5. Repurposing and Repositioning Drugs

To accelerate treatment for GBMs in a cost-effective manner, investigators have turned to repositioning and/or repurposing FDA approved therapeutics with properties likely to confer BBB permeability. Identifying drugs to repurpose can be achieved by in silico screening; for example, repurposing of the antifungal drug itraconazole as an anti-cancer agent [16] or molecular target screening using sequencing and proteomic analysis of the tumors to provide a rational, personalized treatment [17]. Alternatively, anti-cancer drugs are being repositioned as therapeutics for GBM; for example, employing CDK 4/6 inhibitors commonly used to treat breast cancers as anti-GBM therapeutics [18].

Repurposing of FDA approved therapeutics can often utilize the “505(b)(2)” new drug application (NDA) approval pathway. Unlike the standard 505(b)(1) NDA regulatory submission pathway for new chemical entities that require complete safety and effectiveness reports from studies conducted by sponsor, the 505(b)(2) regulatory pathway allows sponsors to include information from published studies and findings of safety and effectiveness from approved products with the same active ingredient even when the studies were not conducted by the sponsor. The 505(b)(2) regulatory submission can significantly reduce the time of NDA approval and reduce product development costs for repurposed approved FDA therapeutics. While repurposing can significantly reduce the time, cost, and risk of drug development, drug repurposing is not without financial, legal, and regulatory pitfalls and challenges. FDA approved therapies are protected against competition by both patents and data exclusivity granted at the time of FDA approval, which enable companies to recover development costs for new medicines. Patent terms are set for 20 years and protect the product’s intellectual property while exclusivity restricts the use of data generated by the drug innovator and prohibits approval of generic versions for a set time. The exclusivity period is 5 years for new chemical entities, 7 years for orphan drugs, and an additional 3 years of exclusivity for new clinical investigation of a previously active agreement with 6 months added to both pediatric and exclusivity for pediatric development. Biologic products with often complex, costly, and lengthy development may be granted up to 12 years of exclusivity. For off-patent products, development of the novel indication must be assessed relative to competition from the available generic market. For products under patent protection or within the exclusivity period, licensing agreements or partnerships must be established with the innovator company for product development. Drug repurposing also faces challenges attracting funding and industry support without clear marketing opportunities. Undoubtedly, collaboration between industry and/or biotechnology and academia is important to provide pharmaceutical expertise and funding sources that meet patient, investor, and regulatory needs for successful drug repositioning [19][20][21].

References

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  2. Glioblastoma Multiforme. Available online: https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Glioblastoma-Multiforme (accessed on 16 October 2020).
  3. Zhang, P.; Xia, Q.; Liu, L.; Li, S.; Dong, L. Current Opinion on Molecular Characterization for GBM Classification in Guiding Clinical Diagnosis, Prognosis, and Therapy. Front. Mol. Biosci. 2020, 7, 562798.
  4. Oh, S.; Yeom, J.; Cho, H.J.; Kim, J.-H.; Yoon, S.-J.; Kim, H.; Sa, J.K.; Ju, S.; Lee, H.; Oh, M.J.; et al. Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities. Nat. Commun. 2020, 11, 3288.
  5. Verhaak, R.G.W.; Hoadley, K.A.; Purdom, E.; Wang, V.; Qi, Y.; Wilkerson, M.D.; Miller, C.R.; Ding, L.; Golbuc, T.; Mesirov, J.P.; et al. An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer Cell 2010, 10, 98.
  6. Pearson, J.R.D.; Regad, T. Targeting cellular pathways in glioblastoma multiforme. Sig. Transduct. Target Ther. 2017, 2, 17040.
  7. Ostrom, Q.T.; Cioffi, G.; Gittleman, H.; Patil, N.; Waite, K.; Kruchko, C.; Barnholtz-Sloan, J.S. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol. 2019, 21, v1–v100.
  8. Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.B.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N. Engl. J. Med. 2005, 352, 987–996.
  9. Kitange, G.J.; Carlson, B.L.; Schroeder, M.A.; Grogan, P.T.; Lamont, J.D.; Decker, P.A.; Wu, W.; James, C.D.; Sarkaria, J.N. Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts. Neuro Oncol. 2009, 11, 281–291.
  10. Bahadur, S.; Sahu, A.K.; Baghel, P.; Saha, S. Current promising treatment strategy for glioblastoma multiform: A review. Oncol. Rev. 2019, 13, 417.
  11. Fabian, D.; Del Pilar Guillermo Prieto Eibl, M.; Alnahhas, I.; Sebastian, N.; Giglio, P.; Puduvalli, V.; Gonzalez, J.; Palmer, J.D. Treatment of Glioblastoma (GBM) with the Addition of Tumor-Treating Fields (TTF): A Review. Cancers 2019, 11, 174.
  12. Sharma, P.; Debinski, W. Receptor-Targeted Glial Brain Tumor Therapies. Int. J. Mol. Sci. 2018, 19, 3326.
  13. Yadavalli, S.; Yenugonda, V.M.; Kesari, S. Repurposed Drugs in Treating Glioblastoma Multiforme: Clinical Trials Update. Cancer J. 2019, 25, 139–146.
  14. Tan, S.K.; Jermakowicz, A.; Mookhtiar, A.K.; Nemeroff, C.B.; Schürer, S.C.; Ayad, N.G. Drug Repositioning in Glioblastoma: A Pathway Perspective. Front. Pharmacol. 2018, 9, 218.
  15. van Tellingen, O.; Yetkin-Arik, B.; de Gooijer, M.C.; Wesseling, P.; Wurdinger, T.; de Vries, H.E. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist. Updates 2015, 19, 1–12.
  16. Pounds, R.; Leonard, S.; Dawson, C.; Kehoe, S. Repurposing itraconazole for the treatment of cancer. Oncol. Lett. 2017, 14, 2587–2597.
  17. Thyparambil, S.P.; Liao, W.-L.; An, E.; Bhalkikar, A.; Heaton, R.; Sylvester, K.G.; Ling, X.B. Proteomic profiling to identify therapeutics targets in glioblastoma (GBM). J. Clin. Oncol. 2020, 38, 2555.
  18. Lubanska, D.; Porter, L. Revisiting CDK Inhibitors for Treatment of Glioblastoma Multiforme. Drugs R D 2017, 17, 255–263.
  19. Breckenridge, A.; Jacob, R. Overcoming the legal and regulatory barriers to drug repurposing. Nat. Rev. Drug Discov. 2019, 18, 1–2.
  20. Pushpakom, S.; Iorio, F.; Eyers, P.A.; Escott, K.J.; Hopper, S.; Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; et al. Drug repurposing: Progress, challenges and recommendations. Nat. Rev. Drug Discov. 2019, 18, 41–58.
  21. Kato, S.; Moulder, S.L.; Ueno, N.T.; Wheler, J.J.; Meric-Bernstam, F.; Kurzrock, R.; Janku, F. Challenges and perspective of drug repurposing strategies in early phase clinical trials. Oncoscience 2015, 2, 576–580.
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