**6. GBM treatment**

GBM tumors show a large number of aberrations with a pronounced mitotic activity, neoan‐ giogenesis, and necrosis. Its proliferative rate is three to five times more than the proliferative rate in AA [53].

On the basis of a recent GBM classification as proneural, neural, classical, and mesenchymal, diverse types of treatments must be created to make a molecular personalized therapy [6] (**Table 1**). Performing molecular assays is complex, as their cost may be an obstacle for a routine use.


**Table 1.** Effects on survival of different treatments for GBM patients and their side effects.

The standard treatment for GBM patients includes brain radiation, a maximal surgery and .chemotherapy with the alkylating agent TMZ.

A larger number of new drugs and virus‐based therapy are being evaluated in phase II and III trials as well.

In a phase III trial including recently diagnosed GBM patients, the median overall survival (OS) for GBM patients was 14.6 months with chemotherapy and RT, and 12.1 months with RT alone with a median follow‐up of 28 months [63].

In phase III of another study, 978 patients received standard radiation and TMZ with or without Bevacizumab, an angiogenesis inhibitor used at 10 mg/kg, every 2 weeks with a median follow‐up of 20.5 months. The OS between bevacizumab group and placebo group was no different, and side effects such as hypertension, thromboembolic events, intestinal perforation, and neutropenia were more common in the bevacizumab group. The progression‐ free survival (PFS) was significantly improved in the experimental arm (10.7 vs 7.3 months, *P* = 0.007) [64]. In another phase (III) trial with 458 patients, newly diagnosed GBM received radiation and TMZ with or without bevacizumab (10 mg/kg each for 2 weeks and TMZ for six cycles). With bevacizumab monotherapy (15 mg/kg), the median of PFS was of 10.6 months in the bevacizumab group as compared to 6.2 months in the placebo group.

## **6.1. Aromatase inhibitors (AIs)**

**6. GBM treatment**

72 Neurooncology - Newer Developments

**Treatment Overall survival (OS)**

rate in AA [53].

use.

Nimotuz umab/RT

III trials as well.

GBM tumors show a large number of aberrations with a pronounced mitotic activity, neoan‐ giogenesis, and necrosis. Its proliferative rate is three to five times more than the proliferative

On the basis of a recent GBM classification as proneural, neural, classical, and mesenchymal, diverse types of treatments must be created to make a molecular personalized therapy [6] (**Table 1**). Performing molecular assays is complex, as their cost may be an obstacle for a routine

TMZ/RT 14.6 months 6.9 months Myelosuppression Stupp (2005) RT 12.1 months 5.0 months Skin reactions, cardiac complications Stupp (2005)

Cilengitide/RT26.3 months 13.5 months Stupp (2014)

22.3 months 7.7 months Headache, nausea, vomiting, anemia,

Nimustine 28.4 months 18.9 months Chest pain and cianosis peribucal Kim (2011) Enzastaurin 17.1 months 9 months Lymphopenia Wick (2013) Tipifarnib 80.3 weeks 18.1 weeks Headache, nausea, vomiting Ducassou (2013)

myalgia

cholesterol in the blood, low phosphorus

The standard treatment for GBM patients includes brain radiation, a maximal surgery

A larger number of new drugs and virus‐based therapy are being evaluated in phase II and

In a phase III trial including recently diagnosed GBM patients, the median overall survival (OS) for GBM patients was 14.6 months with chemotherapy and RT, and 12.1 months with RT

thromboembolism, gastrointestinal perforation

gastrointestinal perforation

**Side effects Author**

Gilbert (2014) Chinot (2014)

Westphal (2015)

Hainsworth (2012)

**Progression‐free survival (PFS)**

Bev/TMZ /RT 20.5 months 10.7 months Myelosuppression, arterial

Everolimus 13.9 months 11.3 months Anemia, higher levels of

**Table 1.** Effects on survival of different treatments for GBM patients and their side effects.

and .chemotherapy with the alkylating agent TMZ.

alone with a median follow‐up of 28 months [63].

Bev 15.7 10.6 Arterial thromboembolism, arterial

The conversion of androstenedione and testosterone to estrogens can be blocked by the aromatase inhibitors; these pharmacological agents have a high specific activity to reduce, importantly, estrogen production. The AIs are classified in two types: I.––steroid inhibitors and II.––nonsteroid inhibitors; they are reactive species that bind covalently and irreversibly or noncovalently and reversibly to aromatase, respectively. The latter class interacts with the heme cofactor by employing its azole moiety. Third generation inhibitors are composed of triazole derivatives: anastrozole, letrozole, and the steroidal examestane. These inhibitors provided greater clinical benefits with a robust aromatase inhibition of 98% or more. The aromatase inhibitors have been successfully used for the treatment of estrogen receptor‐ positive breast cancer in postmenopausal women [65]. Letrozole has a more potent inhibitory effect on estrogen synthesis than anastrozole [66]. Letrozole has been tested in a GBM model using Sprague–Dawley rats orthotopically implanted with C6 cells. Imaging analysis employ‐ ing μPET/CT showed an important reduction in the volume of tumor (>75%) after 8 days of letrozole treatment (4 mg/kg/day) [67].

The AIs, namely 3b‐hydroxyandrost‐4‐en‐17‐one (1), androst‐4‐en‐17‐one (12), 4a,5a‐epoxy androstan‐17‐one (13a), and 5a‐androst‐2‐en‐17‐one (16), induced an antiproliferative effect on MCF7 breast cancer cells, and this effect was due to a cell cycle arrest and cell death by apoptosis [68]. Table 1 shows different treatments for GBM and their effect on OS. It also exhibits the progression‐free survival, with the side effects observed in these studies.

#### **6.2. Hormone release growth hormone (GHRH) inhibitors**

GHRH inhibitors had been used for the treatment of various cancers or disorders that express growth hormone (GH) or GHRH production. GHRH antagonists suppress GH or insulin‐like growth factor (IGF‐1) in transgenic mice overexpressing the *GHRH* gene; GHRH antagonists can inhibit the rat pituitary tumor cells overexpressing the GHRH receptors (p‐GHRH‐R). These antagonists also inhibit GH secretion [70]. There is evidence that GHRH antagonists are well tolerated in humans; however, more phase I–III clinical trials are necessary to probe the efficiency of these antagonists [71]. GHRH antagonists inhibit cancers that depend on IGF‐1 as a growth factor [72–74]. GHRH antagonists can also inhibit various autocrine factors such as GHRH, GH, or VEGF by binding to the tumoral GHRH receptors, resulting in a tumor growth suppression [75,76]. In addition, GHRH antagonists could provoke tumor cell death by active cell pathways producing apoptosis [77,78].

The presence of the GHRH‐R variant SV1 differs from the pGHRH by a short segment of the extracellular ligand‐binding domain of the receptor protein in normal tissue and in various neoplastic tumors, lymphomas, small‐cell lung carcinomas, pancreatic cancer, glioblastomas, and prostate cancer [79–81]. In several experimentally formed tumors, GHRH antagonist inhibits the growth and metastasis of cells expressing these receptor types. This inhibition occurs by binding to the full length of the GHRH‐R or SV1 [79,80,82]. Kovácks et al., 2010 observed a strong GH release inhibition by the JV‐1‐63, reducing tumor growth (46%) of DBTRG‐05 glioblastomas. Their experiments were conducted on nude mice. JV‐1‐63 antago‐ nists caused an upregulation of mRNA expression of pGHRHR and downregulation of SV1 expression in vitro [82].

The use of aromatase and GHRH inhibitors could have a clinical use in patients with GBM once adequate phase II or III clinical trials are made.
