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Castro, C.; Nunez Abades, P. PKC Targeted Glioblastoma Treatment. Encyclopedia. Available online: https://encyclopedia.pub/entry/8841 (accessed on 11 November 2025).
Castro C, Nunez Abades P. PKC Targeted Glioblastoma Treatment. Encyclopedia. Available at: https://encyclopedia.pub/entry/8841. Accessed November 11, 2025.
Castro, Carmen, Pedro Nunez Abades. "PKC Targeted Glioblastoma Treatment" Encyclopedia, https://encyclopedia.pub/entry/8841 (accessed November 11, 2025).
Castro, C., & Nunez Abades, P. (2021, April 20). PKC Targeted Glioblastoma Treatment. In Encyclopedia. https://encyclopedia.pub/entry/8841
Castro, Carmen and Pedro Nunez Abades. "PKC Targeted Glioblastoma Treatment." Encyclopedia. Web. 20 April, 2021.
PKC Targeted Glioblastoma Treatment
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9040381

Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is therefore necessary to identify new therapeutic targets to fight GBM progression and recurrence. Some publications have pointed out the role of glioma stem cells (GSCs) as the origin of GBM. These cells, with characteristics of neural stem cells (NSC) present in physiological neurogenic niches, have been proposed as being responsible for the high resistance of GBM to current treatments such as temozolomide (TMZ). The protein Kinase C (PKC) family members play an essential role in transducing signals related with cell cycle entrance, differentiation and apoptosis in NSC and participate in distinct signaling cascades that determine NSC and GSC dynamics. Thus, PKC could be a suitable drugable target to treat recurrent GBM. Clinical trials have tested the efficacy of PKCβ inhibitors, and preclinical studies have focused on other PKC isozymes.

glioblastoma protein kinase C glioma stem cells neurogenesis neural stem cells temozolomide enzastaurin epidermal growth factor receptor neuregulin

1. Introduction

Gliomas account for 30% of all tumors of the central nervous system (CNS) and 80% of all malignant brain tumors in adults [1]. Although diffuse gliomas are considered as rare disorders, approximately 100,000 people worldwide are diagnosed with this pathology every year, with it being the second most common cancer in children and adolescents (26% of all cancers) [2][3][4]. Glioma incidence varies with age, sex, ethnicity, tumor histology, and between populations around the world [5].

Based on histopathological criteria and malignancy grade, gliomas are classified as astrocytomas and oligodendrogliomas (OD), either diffuse (grade II) or anaplastic (grade III) and glioblastomas (GBM; grade IV). Briefly, histological features used in the clinical diagnosis of gliomas include: nuclear atypia (grade III), in addition to necrosis and microvascular changes (grade IV). In addition, these latter tumors exhibit high infiltrative and proliferative capacity and increased mitotic activity compared to grade II lesions [6]. This review focuses on GBMs as they are the most common (54% of all gliomas) and the most aggressive in adults, with a median overall survival (OS) of ≈15 months. Additionally, GBM has a high incidence of recurrency (>90%), despite intensive clinical management including surgery, radiotherapy and adjuvant chemotherapy. GBM can appear at any age but the peak incidence is between 75 to 84 years [7]. The incidence of these tumors is approximately 50% higher in males compared to females [8] and it differs substantially between ethnic groups, e.g., it is higher in Caucasians as compared to black populations [7][9][10]. As regards their location, they are most commonly situated in the supratentorial region (frontal, parietal, temporal and occipital lobes), with the highest incidence in the frontal lobe [11], while they are rarely located in the cerebellum [12]. Furthermore, the incidence of GBM increases in patients with hereditary tumor syndromes, such as Turcot syndrome [13] and Li-Fraumeni syndrome [14].

Since diagnosis and prognosis of gliomas based on histological features is insufficient, the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO) incorporated molecular parameters to improve clinical interventions in patients with this pathology [15]. Amongst the molecular genetic alterations used to redefine glioma entities, the most common are mutations in the isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) genes and the 1 p/19q co-deletion status [16][17][18]. According to the IDH condition, gliomas are divided into IDH-mutant (IDH1 R132 or IDH2 R172) and IDH-wild-type; 90% of GBMs (usually primary or “de novo” GBMs) are wild-type for IDH and have a poor prognosis (median OS of 1.2 years). Meanwhile, secondary GBM (10%) develops through progression from a low-grade lesion and is associated with a better prognosis and survival rate due to the IDH mutation (median OS of 3.6 years) [1][6][19][20][21]. This biomarker, used in combination with the loss of heterozygosity in chromosomal arms 1p/19q for the diagnosis of grade II and III oligodendrogliomas, is linked to favorable clinical behaviors [20][21]. In the case of tumors which cannot be classified into any of these groups due to lacking sufficient pathological and genetic information (i.e., absence of appropriate diagnostic molecular testing or inconclusive results), the 2016 CNS WHO assigned the NOS (Not Otherwise Specified) category, which should be the subject to future studies [15][16]. Nonetheless, other biomarkers with predictive value of the progression and response to the first-front therapeutics are also frequently used in the clinic. The loss of ATRX (alpha thalassemia/mental retardation syndrome X-linked) is a recurrent marker of astrocytoma and secondary GBM and is associated with IDH and TP53 mutations, which are linked to a good outcome [22]. Hypermethylation of the MGMT (O6-methylguanine-DNA methyltransferase) promoter is considered an important predictor of a good response to chemotherapy with temozolomide (TMZ) in glioma patients [23][24]. Telomerase reverse transcriptase (TERT) promoter mutations have been detected in more than 50% of primary adult GBM and are correlated with increased telomerase activity [24][25], having been linked to lower survival times in GBM patients [26]. However, in combination with IDH1 and MGMT mutations, these mutations are good predictors of grade II and grade III gliomas [27]. Finally, EGFR (epidermal growth factor receptor) expression, without loss of PTEN (phosphatase and tensin homolog), explains the sensitivity of gliomas to tyrosine kinase inhibitors [28]. In conclusion, the use of molecular traits is assisting with the classification of gliomas, the high biological heterogeneity of which require the use of different experimental models for their study [29] and different strategies of clinical management.

2. Clinical Trials Using PKC Targeting Drugs

Several clinical trials conducted over the past 20 years have tested the effects of PKC inhibitors in GBM, mainly classical PKC inhibitors in the treatment of recurrent GBM. Treatment of relapsing patients is still challenging, as current clinical management involves surgery, radiotherapy and TMZ treatment with no better outcomes having been found by using alternative drugs (reviewed in Finch et al., 2021 [30]).

The first clinical trials using PKC targeting drugs tested the efficacy of tamoxifen. This nonsteroidal agent with high lipid solubility is able to cross the blood–brain barrier (BBB) and reach the tumor. Tamoxifen elicits the association of PKC to the membrane, followed by an irreversible activation, and subsequent down-regulation of the enzyme, leading to cell growth inhibition [31], cellular apoptosis, and at high doses, chemoresistance reversion [32][33]. For the treatment of GBM, Couldwell and colleagues and Brandes and colleagues were the first to use high-doses of tamoxifen to inhibit PKC, based on in vitro assays that evaluated apoptosis in GBM cells either alone, or in combination with procarbazine in phase II clinical trials. The most relevant finding was an increase in radiosensitivity [34][35]. However, the OS rates shown in these studies were 6.8 and 7.2 months, and the time to progression was 3.3 months. More promising results were observed in a more recent study in which tamoxifen was tested in combination with TMZ. In this study the observed median time to progression was 9.5 months and the OS was 17.5 months [36]. Additional clinical trials have tested tamoxifen in combination with other agents such as procarbazine or TMZ to affect PKC functionality and other targets [37][38][39] (see Table 1 for further details).

Table 1. Summary of protein kinase C-related clinical trials for the treatment of glioblastoma.

  Target Authors and Year Trial Phase Nº Patients Dose PFS OS
Tamoxifen PKC Couldwell et al 1996 [34] Phase II trial 32 200 mg/day (100 mg twice daily) of tamoxifen was administered to males 160 mg/day (80 mg twice daily) of tamoxifen was administered to females n.d. 7.2 months
Tamoxifen + Procarbazine PKC + DNA Brandes et al 1999 [38] Phase II trial 53 100 mg/day of tamoxifen + 100 mg/m2/day of procarbazine were administered for 30 days with 30-day intervals between cycles 3 months (median) 6.2 months
Tamoxifen + TMZ PKC + DNA Spence et al. 2004 [39], Cristofori et al. 2013 [36] Phase II trial 16 40 mg twice daily of tamoxifen for 1 week and was escalated to 60 mg, 80 mg then 100 mg + 75 mg/m2/day of TMZ for 6 weeks, repeated every 10 weeks, with a maximum of 5 cycles n.d. 6 months
  PKC + DNA Cristofori et al. 2013 [36] Phase II trial 32 80 mg/m2/day of tamoxifen + 75–150 mg/m2/day of TMZ was administered for one week on/one week off 9.5 months (median) 17.5 months
Tamoxifen + Radiation PKC Robins et al. 2006 [35] Phase II trial 75 80 mg/m2/day of tamoxifen, divided in 4 doses of 20 mg/m2 every 6 h, was administered during and after of 60 Gy in 30 fractions × 2 Gy of radiotherapy 2.9 months (median) 11.3 months
Enzastaurin PKCβ Kreisl et al. 2009 [40] Kreisl et al. 2010 [41] Phase I trialPhase I/II trial 2215 (Phase I) 103 (Phase II) 800 mg/day of enzastaurin and 400 mg twice daily and 500 mg/day and 250 mg twice daily for patients not taking EIAEDs and 1000 mg/day and 500 mg twice daily for patients taking EIAEDs in phase I, patients who were taking EIAEDs, received 525, 700 and 900 mg/day of enzastaurin and patients in phase II, who were not taking EIAEDs, received 500 or 525 mg/day of enzastaurin 1.4 months (median) 1.3 months (median) 7% (at 6-month) 5.7 months 4.6 months
Enzastaurin vs. Lomustine PKCβ vs. DNA/Stathmin-4 Wick et al. 2010 [42] Phase III trial 266 500 mg/day of enzastaurin vs. 100 to 130 mg/m2 of lomustine on day 1 with cycles of 6 weeks Enzastaurin: 1.5 months, 11.1% (median, at 6-month); Lomustine: 1.6 months, 19% (median, at 6-month) Enzastaurin: 6.6 months Lomustine: 7.1 months
Enzastaurin + TMZ PKC β + DNA Rampling et al. 2012 [43] Phase I trial 28 250 mg/day (once daily); 500 mg/day (once daily); 500 mg/day (250 mg twice daily) of enzastaurine. 150–200 mg/m2 TMZ 5.5 months (median) 11.7 months
Enzastaurin + TMZ with radiation PKC β + DNA Butowski et al. 2010 [44] Phase I trial 12 Radiation therapy 1.8–2.0 Gy × 30 fractions 5 days a week for 6 weeks + Enzastaurin 250–500 mg/daily + TMZ 75 mg/m2 n.d. n.d.
Enzastaurin + Bevazizumab PKC β + VEGF Odia et al. 2016 [45] Phase II trial 40 Enzastaurin 500 or 875 mg/day + bevacizumab 10 mg/kg intravenously biweekly 2.0 months 7.5 months
Aprinocarsen PKC α Grossman et al. 2005 [46] Phase II trial 21 2 mg/kg/day of aprinocarsen was administered for 21 days per month 1.2 months (median) 3.4 months
PFS, progression-free survival; OS, overall survival; EIAEDs: enzyme-inducing anti-epileptic drugs; Gy: gray; n.d: not determined; OS: overall survival; PFS: progression-free survival; PKC: protein kinase C; TMZ: temozolomide.

 

Undoubtedly, the most relevant clinical trials implicating PKC in GBM so far have analyzed the effects of enzastaurine. This small molecule is an inhibitor of PKC β that has been used for the treatment of a variety of tumors and, similarly to tamoxifen, is a lipid soluble compound that can cross the BBB. Enzastaurin was originally developed as an anti-angiogenic agent based on the role of PKC β in angiogenesis [47][48][49][50]. However, its specificity is not very high for PKC β since, at higher concentrations, the drug can inhibit other PKC isoforms including PKCα [48][49]. Despite this, enzastaurin has shown a longer half-life than TMZ (12–40 h vs. 1.8 h) and remarkable radiographic response rates in recurrent high-grade gliomas [43][44]. Although a phase III clinical trial failed to demonstrate such efficacy after comparing the monotherapies of enzastaurin and lomustine in recurrent GBM, the PFS was 1.5 months and OS was 6.6 months [42]. Therefore, these trials did not improve the effectiveness of current treatments, even in combination with lomustine, a nitrosourea that interacts with DNA, commonly used as a chemoterapeutic agent [42][40][41]. Other strategies have been explored—such as a combination with bevacizumab—with no further improvement [45]. Therefore, clinical trials using the PKC inhibitor enzastaurin have not succeeded at limiting GBM progression and invasion, either alone, or in combination with TMZ or other compounds. In addition to tamoxifen and enzastaurin, a trial to test the PKCα inhibitor aprinocarsen has been carried out without success [46].

As stated above, the tumor microenvironment and intra-tumor heterogeneity should be considered as responsible for the lack of improvement found in phase III trials with enzastaurin. Alteration of PKC expression and activity among the different cell types within the tumor needs also to be considered. Alternatively, enzastaurin itself might modify PKC expression or alter the signaling cascades that interact with PKC activity, creating resistance. Thus, identification of signaling cascades associated with PKC and compounds that target these molecules might help in the design of additional therapies that overcome intra-tumor heterogeneity and TME induced evolution.

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