**8. Emergent treatments strategies**

As the field of neuro-oncology continues to progress, numerous novel therapies have been tried and tested. Results from preclinical and clinical studies applying new treatments alone or in combination with conventional methods are promising.

GBM has abnormalities in **cellular signal transduction pathways**. All these pathways include receptor tyrosine kinases (RTKs) like vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), etc., and share common mechanisms of activation and intracellular signaling, meaning RAS or phosphoinositol-3-kinase (PI3K) pathways. Genetic alterations of RTK/RAS/PI3K occur in about 88% of primary GBMs; the pathways are overactivated, allowing uncontrolled cellular proliferation, survival and invasion [79, 80]. Targeted molecular drugs have been developed to inhibit aberrantly activated signaling pathways in the clinical setting.

**Increased epidermal growth factor receptor (EGFR) signaling** has been reported in approximately 45% of GBM [79, 80]. It results in tumor cell proliferation, invasiveness, migration, angiogenesis and inhibition of apoptosis. Moreover, in the clinical setting, EGFR overexpression is associated with resistance to RT while EGFR inhibitions increased sensibility to RT [81]. Inhibitors of EGFR have been developed to block-specific pathways, but the results are disappointing. These include: monoclonal antibodies (cetuximab and nimotuzumab), small molecule tyrosine kinases inhibitors TKIs (gefitinib and erlotinib), a dual EGFR and ErbB-2 inhibitor (lapatinib), a pan-ErbB inhibitor (canertinib), a dual EGFR and vascular endothelial growth factor receptor (VEGFR) inhibitor (vandetanib), irreversible EGFR inhibitors (BIBW 2992 and PF-00299804), etc. It is to be noted that the ErbB family of proteins contains four receptor tyrosine kinases, structurally related to EGFR, marked as ErbB-1 to ErbB-4. ErbB-1 and ErbB-2 are found in many human cancers.

**Overexpression of alpha subtype of PDGF receptor (PDGFR)** occurs in about 13% of GBM [79]. Imatinib mesylate and tandutinib are inhibitors of PDGFR and other molecules involved in intracellular signaling pathways.

**VEGF** is a key factor implicated in tumor neoangiogenesis. GBM is a highly vascular tumor, that depends on vascular proliferation for growth. Recent evidence suggests vasculogenic mimicry in GBM, meaning formation of vessel-like network by tumor cells, allowing a blood supply for tumor growth. This process differs from angiogenesis, it is happening without the presence of endothelial cells. Angiogenesis is driven primarily by tumor-secreting VEGF-A (one member of the VEGF family), but there are many secreted proangiogenic factors [82]. The level of VEGF in HGG is greater than 10-fold compared with LGG [83]. Thus, drugs have been developed to interfere with angiogenesis by directly blocking ligand (VEGF) or receptor (VEGFR) or by targeting proangiogenic molecules that function by alternative mechanisms [84]. Of all targeted biological agents, only **bevacizumab** (Avastin) has demonstrated efficacy. It is a humanized monoclonal antibody that selectively blocks VEGF and so the BBB becomes more stable, with a resultant decrease in vascular permeability and edema, such that the corticosteroid doses can be reduced or suspended. Bevacizumab may be useful during and after RT, because of reduction of peritumoral edema, sometimes refractory to corticosteroid drugs and because of reduction of radiation necrosis rate following improving oxygenation. It has been approved by FDA (2009) as a single agent in the treatment of recurrent GBM following prior therapy, based on improvement in progression-free survival (that however did not translate into an improvement in overall survival) and a modest toxicity profile. Patients treated with bevacizumab inevitably relapse and sometimes an aggressive, invasive "gliomatosis" pattern of recurrence, unresponsive to subsequent therapy is observed. In addition to bevacizumab, there are many inhibitors of VEGF/VEGFR and other relevant targets under investigation, including: vatalanib, cediranib, sunitinib, sorafenib, vandetanib, VEGF trap, ramucirumab, pazopanib, etc. Dually targeted VEGFR/PDGFR inhibitors may prove useful, because of role of PDGFR in pericyte recruitment.

antiproliferative properties with minimal toxicity. It has been approved (FDA 2015) as an alternative treatment for adult patients having a newly diagnosed supratentorial GBM following debulking surgery and completion of RT, with concomitant SoC chemotherapy. It has also been approved (FDA, 2011) for the treatment of adult patients with supratentorial confirmed recurrences of GBM, to be used as a monotherapy, as an alternative to standard medical therapy after surgical and radiation options have been exhausted (Novocure, 2017). Current evidence supports the use of TTFs as a therapeutic option. Stupp et al. analyzed 315 patients with GBM who had completed standard chemoradiation therapy, adding TTFields to maintenance TMZ chemotherapy and found a significantly prolonged progression-free survival and overall survival. Median progression-free survival was 7.1 months in the TTFields plus TMZ group and 4 months in the TMZ alone group. Median overall survival was 20.5 months in the

As the field of neuro-oncology continues to progress, numerous novel therapies have been tried and tested. Results from preclinical and clinical studies applying new treatments alone

GBM has abnormalities in **cellular signal transduction pathways**. All these pathways include receptor tyrosine kinases (RTKs) like vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), etc., and share common mechanisms of activation and intracellular signaling, meaning RAS or phosphoinositol-3-kinase (PI3K) pathways. Genetic alterations of RTK/RAS/PI3K occur in about 88% of primary GBMs; the pathways are overactivated, allowing uncontrolled cellular proliferation, survival and invasion [79, 80]. Targeted molecular drugs have been developed to inhibit aberrantly acti-

**Increased epidermal growth factor receptor (EGFR) signaling** has been reported in approximately 45% of GBM [79, 80]. It results in tumor cell proliferation, invasiveness, migration, angiogenesis and inhibition of apoptosis. Moreover, in the clinical setting, EGFR overexpression is associated with resistance to RT while EGFR inhibitions increased sensibility to RT [81]. Inhibitors of EGFR have been developed to block-specific pathways, but the results are disappointing. These include: monoclonal antibodies (cetuximab and nimotuzumab), small molecule tyrosine kinases inhibitors TKIs (gefitinib and erlotinib), a dual EGFR and ErbB-2 inhibitor (lapatinib), a pan-ErbB inhibitor (canertinib), a dual EGFR and vascular endothelial growth factor receptor (VEGFR) inhibitor (vandetanib), irreversible EGFR inhibitors (BIBW 2992 and PF-00299804), etc. It is to be noted that the ErbB family of proteins contains four receptor tyrosine kinases, structurally related to EGFR, marked as ErbB-1 to ErbB-4. ErbB-1

**Overexpression of alpha subtype of PDGF receptor (PDGFR)** occurs in about 13% of GBM [79]. Imatinib mesylate and tandutinib are inhibitors of PDGFR and other molecules involved

TTFields plus TMZ group and 15.6 months in the TMZ-alone group [78].

or in combination with conventional methods are promising.

**8. Emergent treatments strategies**

24 Brain Tumors - An Update

vated signaling pathways in the clinical setting.

and ErbB-2 are found in many human cancers.

in intracellular signaling pathways.

Other antiangiogenic approach targets **the integrins** *α***v***β***3 and** *α***v***β***5** that are overexpressed by tumor endothelial cells. They are transmembrane receptors that interact with extracellular matrix proteins to facilitate angiogenesis and invasion. Cilengitide inhibits these integrins.

There are clinical studies focused on **substances that inhibit intracellular signaling molecules**. Overactivation of the PI3K/Akt/mTOR signaling in GBM has been observed, because of receptor tyrosine kinase overactivity, mutated oncogenic PI3K subunits, and/or loss of PTEN tumor suppressor activity. Several mTOR inhibitors are currently tested, including sirolimus, temsirolimus, everolimus, and ridaforolimus. Enzastaurin is an inhibitor of protein kinase C-β2 that suppresses PI3K/Akt pathway. Overactivation of RAS/RAF/mitogen-activated protein kinase pathway in malignant glioma has provided the rationale to study farnesyl transferase inhibitors (farnesylation is a critical step in activation of RAS). Tipifarnib, lonafarnib and sorafenib may inhibit farnesyltransferase. Histone deacetylase inhibitors (vorinostat, romidepsin, valproic acid, etc.) prevent gene transcription, resulting in cell cycle arrest, differentiation, and/or apoptosis of tumor cells. Clinical trials are in progress.

**Immunotherapy** has become a promising cancer treatment, which allows for synergistic multimodal strategies. There are different immunotherapeutic approaches in GBM, including active immunotherapy (tumor vaccination therapy) and passive immunotherapy (antibodybased immunotherapy, adoptive cell therapy and other immune-modulatory therapy). **Tumor**  **vaccination therapy** uses administration of the antigens to activate an antitumor immune response. There is a vaccine targeting the mutant of epidermal growth factor receptor EGFRvIII (only expressed in GBM cells in about 20–25% of cases) – rindopepimut. Vaccination with dendritic cells is based on their ability to absorb all kinds of antigens and to secrete interleukin-2, thus activating T lymphocytes and initiating an efficient and specific immune response [85]. The application of tumor-derived heat shock proteins as tumor antigen carrier may be effective in boosting immune response. **Antibody-based immunotherapy** refers to the use of specific interaction between antibodies and antigens to block negative immune regulatory molecules that would have been preventing activated T cells from attacking the cancer cells. The most promising class of drugs that emerged is based on immune checkpoint inhibitors. Nivolumab and pembrolizumab are antibodies targeting the receptor programmed cell death-1 (PD-1) receptor of lymphocytes. Ipilimumab is an antibody that binds cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), which would have inhibiting cytotoxic T lymphocyte to destroy cancer cells. **Adoptive cell therapy** is based on infusion of activated immune effector cells into cancer patients with the goal to enhance antitumor immunity. Immune effector cells include lymphokine-activated killer (LAK) cells, natural killer (NK) cells, T cells, tumor-infiltrating lymphocytes (TILs), cytotoxic T lymphocyte (CTLs), tumor antigen-specific TCR-transgenic T cells and chimeric antigen receptors-modified T cells (CAR T) [86]. This approach would be beneficial to non-responsive patients and non-immunogenic tumors.

host cells are destroyed, and tumor-associated antigens are released, while progeny virions infect neighboring tumor cells. Finally, a complete destruction of the tumor can be achieved, multiple mechanisms being involved together with direct oncolysis, meaning induction of an effective antitumor immune response, cancer cell starvation by destruction of tumor vasculature, and sometimes the activity of virally encoded therapeutic transgenes. The two most studied oncolytic virus types are adenoviruses and herpes simplex viruses. **Another strategy of gene therapy targets genes that may modulate the tumor microenvironment**, to create unfavorable conditions for tumor growth or enhance the efficacy of therapy. Although there is a limited evidence of a therapeutic benefit of gene therapy to date, it is important to note

Effective treatment in GBM remains one of the most formidable challenge in neuro-oncology. Treatment is multimodal and despite significant advances in diagnostic technology, surgical technique, radiation, chemotherapy and targeted therapy, the prognosis remains poor. Largescale research efforts are required to understand the molecular biology of brain tumors and to discover novel therapies. Synergistic multimodal strategies and individualized treatments are likely to be the best approach of these complex tumors to finally improve survival and

, Tabita Larisa Cazac2

, Stefan Alexandru Artene4

, Oana Alexandru3

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049 27

and Anica Dricu4

,

\*

that these therapies appear to be safe.

**9. Conclusions**

quality of life of the patients.

Ligia Gabriela Tataranu1,2, Vasile Ciubotaru2

, Daniela Elise Tache4

1 University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania

2 Department of Neurosurgery,"Bagdasar-Arseni" Emergency Clinical Hospital, Bucharest,

3 Department of Neurology, University of Medicine and Pharmacy of Craiova, Romania

4 Department of Biochemistry, University of Medicine and Pharmacy of Craiova, Romania

[1] Stupp R et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology. 2009;**10**(5):459-466

\*Address all correspondence to: anica.dricu@live.co.uk

**Author details**

Romania

**References**

Oana Stefana Purcaru4

**Gene therapy** is designed for delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes. There are four types of gene therapy proposed for the treatment of GBM: suicide gene therapy, immunomodulatory gene therapy, tumor-suppressor gene therapy, and oncolytic virotherapy. **Suicide gene therapy** uses genes that encode enzymes able to convert a non-toxic drug into an active cytotoxic compound. The herpes simplex virus (HSV) type 1 thymidine kinase (tk) gene has been used as a "suicide gene", allowing to tumor cells to produce high levels of tk. Ganciclovir is the systemically injected prodrug, that will be converted by tk into a toxic metabolite. This compound is incorporated into DNA of actively proliferating tumor cells, and consequently blocks DNA replication and inhibits cell division. Apoptosis underlies the mechanism of cytotoxicity [87]. Another "suicide gene" is cytosine deaminase (CD), an enzyme capable to convert an antifungal drug, 5-fluorocytosine (5-FC), into the highly toxic compound 5-fluorouracil (5-FU). This is again converted into molecules which interfere with RNA processing and DNA synthesis and apoptosis invariably occurs. **Immunomodulatory gene therapy** induces or augments an enhanced specific antitumoral immune response, overcoming the tumor-induced immunosuppression. **Tumor-suppressor gene therapy** aims to restore the function of a tumor-suppressor gene lost or functionally inactivated in cancer cells. They play a critical role in maintaining genome integrity and in regulating cell proliferation, differentiation, and apoptosis. In GBM, there is at least one tumor-suppressor gene mutated or deleted in all cases; in 91% of patients, 2 or more of these tumor-suppressor genes are inactivated [88]. Correcting the genetic abnormalities in the glioma cells has been demonstrated to suppress tumor growth via induction of apoptosis and cell cycle arrest. Genes encoding p53, p16, or phosphatase and tensin homolog (PTEN) can be candidates for this type of therapy. **Oncolytic virotherapy** employs replication-competent viruses with natural or engineered tropism and activity against tumors. They specifically infect and replicate in target tumor cells. During progeny particle release, tumor host cells are destroyed, and tumor-associated antigens are released, while progeny virions infect neighboring tumor cells. Finally, a complete destruction of the tumor can be achieved, multiple mechanisms being involved together with direct oncolysis, meaning induction of an effective antitumor immune response, cancer cell starvation by destruction of tumor vasculature, and sometimes the activity of virally encoded therapeutic transgenes. The two most studied oncolytic virus types are adenoviruses and herpes simplex viruses. **Another strategy of gene therapy targets genes that may modulate the tumor microenvironment**, to create unfavorable conditions for tumor growth or enhance the efficacy of therapy. Although there is a limited evidence of a therapeutic benefit of gene therapy to date, it is important to note that these therapies appear to be safe.
