ReviewUnderstanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer
Introduction
Glioblastoma (GBM), is an aggressive and invariably lethal form of malignant brain tumour. GBM is highly heterogeneous and invasive, which accounts for the fact that it has one of the worst survival rates across all types of cancers. The highly complex nature of GBM also impacts advances toward the development of better treatments. The best current standard treatment across the globe relies on surgery, radiotherapy and a single drug, temozolomide (TMZ) [1]. The median survival time with optimal treatment is about 14 months, while the 5-year survival rate is close to or below 5% [2]. The uniformly poor prognosis in the majority of GBM patients highlights the importance of research needed to understand the molecular pathways and mechanisms which drive GBM pathology as a means to identify better and safer treatments.
GBM can occur as a primary, de novo tumour, or as a secondary tumour developing from pre-existing lower grade glioma tumours. In primary GBM, tumours develop rapidly, within several months, without evidence of pre-existing symptoms or neoplasms. Secondary GBM arises from a lower grade tumour. For example, diffuse astrocytoma, a grade II tumour, can gradually progress into malignant anaplastic astrocytoma (grade III), and ultimately into GBM (grade IV). Progression from low grade glioma (LGG) to GBM is slow, occurring over the course of several years, which is reflected in the longer median survival time of LGG patients compared to GBM patients [3].
Section snippets
GBM subtypes
In a landmark study by The Cancer Genome Atlas (TCGA) consortium involving the consolidation of clinical data together with DNA sequencing, expression analysis via microarray and RNA sequencing of hundreds of patient tumours, four GBM molecular subtypes have been identified which, in part, explain some variations in clinical the characteristics observed and patient outcomes [4].
Drug resistance
GBM is relatively resistant to therapy, with recurrent GBM being even more resistant, even to highly aggressive treatment and is the result of a complex interplay of factors. A primary reason for poor efficacy of many anticancer drugs which are used for other cancers, is inefficient drug penetrance due to the impediment of the Blood Brain Barrier (BBB) and high tumour interstitial pressure [16,17]. This is compounded by genomic instability induced by widespread alterations in genetic material
MAPK signalling
The activity of the mitogen activated protein kinase (MAPK) pathway is frequently altered in GBM. This pathway has key roles regulating cell proliferation, cell survival and metastasis (J.-Y. [22,23]). High levels of phosphorylated (activated) MAPK has been linked to poor patient survival in GBM [24].
The MAPK pathway can be activated when growth factor ligands such as epidermal growth factor (EGF) bind to their corresponding receptors, which belong to the receptor tyrosine kinase (RTK) family (
cAMP signalling
The cyclic adenosine 3′, 5′-monophosphate (cAMP) pathway regulates multiple cellular functions. Signalling typically begins with the binding of a ligand to a G-protein-coupled receptor (GPCR) [44]. This causes G-proteins to activate the enzyme adenylyl cyclase (AC) which converts adenosine triphosphate (ATP) to the second messenger cAMP (Fig. 3). Subsequently, cAMP can activate several effectors including the cAMP dependent protein kinase A (PKA). An important regulatory mechanism of this
Targeting the PI3K and MAPK pathways
The PI3K and MAPK pathways regulate GBM development and tumour growth but the precise cellular behaviours regulated by each pathway is not fully understood. Given the limited treatment strategies currently available to patients, the development of new drugs which target the PI3K and MAPK pathways could potentially improve overall patient survival and quality of life significantly. In fact, numerous preclinical studies and clinical trials have been undertaken using inhibitors of the PI3K and
The influence of signalling pathways on the GBM microenvironment
Activation of MAPK and PI3K pathways are linked to immunosuppression in GBM. Upregulation of pERK1/2 in the MAPK pathway and inactivation of PTEN in the PI3K pathway are associated with increased expression of PD-L1 on the surface of GBM cells [81,82]. PD-L1 is an immune checkpoint which can induce T-cell apoptosis when interacting with PD-1 on the T-cell surface. GBM tumours harbouring PTEN inactivating mutations are known to upregulate PD-L1 expression in monocytes through IL-10 modulation [83
Conclusions
Backed by the evidence from a vast array of research so far, it seems possible that specific targeting of three key cellular signal transduction pathways may lead to an improved clinical management of difficult to treat cancers, such as GBM. Targeting individual pathways in GBM is unlikely to provide effective tumour control, but using a combinatorial drug approach, each targeting distinct, pivotal positions or nodes in multiple pathways may lead to safer treatment and improved patient outcome.
Acknowledgements
Our laboratories are supported by grants from the CASS Foundation Australia, The Brain Foundation Australia and the Royal Melbourne Hospital Neuroscience Foundation.
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