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tumor suppressor gene, and oncogenic mutations in various to be an effective way to control GBM growth. [32-34] Examples
PI3K isoforms that lead to a constitutively activated of VEGF/VEGFR inhibitors are bevacizumab, already in
pathway. [11,12] Aberrant PAM signaling also favors essential phase III trial, and aflibercept, a VEGF/VEGFR inhibitor
[35]
steps for cell invasion and metastasis in CNS malignancies that also targets placental growth factor. [36] Unfortunately,
[Figure 1]. The implications of aberrant PAM signaling in long-term treatment with aflibercept was reported to induce
angiogenesis, epithelial to mesenchymal transition (EMT) an invasive phenotype of GBM. [37,38]
and immune response modulation is currently under intense
investigation. [13-15] Components of the PAM pathway are In addition, RTK inhibitors such as cediranib (an inhibitor of
therefore being considered as potential drug targets [Table VEGFR, platelet-derived growth factor receptor, fibroblast
1] to inhibit the often fatal events of metastasis and cell growth factor receptor 1, and v-kit Hardy-Zuckerman 4
invasion. [16-18] feline sarcoma viral oncogene homolog), have also been
used with promising results. [39,40] Inhibitors of c-MET such
ANGIOGENESIS as cabozantinib are also being considered, and have been
reported to induce a significant increase in overall survival
Angiogenesis is a process consisting of the generation of of mice bearing GBM xenografts. [41]
blood vessels and is essential for the growth of tumor mass
beyond 1mm in diameter. This process allows tumors However, anti-angiogenic therapies targeting VEGF/
[19]
to become invasive by supporting them with nutrients and VEGFR have had less of an effect than expected. This
[42]
oxygen. Tumor and host cells synthesize and secrete pro- could be because, in highly vascularized tissues like
angiogenic factors, such as vascular endothelial growth the lung and brain, tumors can often proliferate around
factor (VEGF), that activate quiescent endothelial cells existing vessels and hijack them, a process called vessel co-
and induce the formation of new blood vessels from pre- option. [43,44] These pre-existing blood vessels circumvent the
existing vascular structures. [20] need to generate new tumor vasculature, and may explain
the inefficacy of anti-proliferative therapies in GBM, the
The PAM pathway plays a critical role in this most vascularized tumor in humans. [38]
neovascularization process by controlling the hypoxia-
inducible factor 1-alpha (HIF-1α) mediated expression and Autophagy is an evolutionarily conserved, catabolic
secretion of VEGF. [21,22] In cancer cells, VEGF stimulation process that maintains cellular biosynthesis through the
can be mediated by chronic stimulation by growth factors, degradation and recycling of proteins and organelles to
such as insulin-like growth factor-1 (IGF-1); constitutive support metabolism and survival during starvation. This
activation of PI3K; or constitutive activation of AKT due to process has been shown to have a complex relationship
inactivation of PTEN. [23,24] The important role of the PAM with angiogenesis induction in various malignancies.
pathway in angiogenesis has been confirmed in various While some studies have reported that autophagy inhibits
malignancies where inhibition of pan-PI3K by LY294002 angiogenesis, [45,46] other studies have found that induction
and downregulation of p110α (or recently, PI3KC2α) were of autophagy promoted cancer and its inhibition prevented
shown to block tumor vascularization. [15,22,25] In myeloid angiogenesis. [47,48] This illustrates the dual role that
cells, PI3Kϒ was reported to be involved in the activation autophagy plays in cancer, acting as a pro-survival or pro-
of integrin α4β1, leading to myeloid cell invasion into death mechanism depending on the tumor type and stage. [49]
tumors and, in turn, to tumor angiogenesis. [26]
Autophagy is induced by different cellular stress-mediated
In GBM, the most aggressive glioma subtype, the PAM signaling pathways, the inputs of which are integrated by
pathway also plays a crucial role in the induction of the protein kinase mammalian target of rapamycin (mTOR).
invasion, angiogenesis and the expression of VEGF in The mTOR complex 1 (mTORC1) is a negative regulator
cells. [24,27] Therefore, new small molecule inhibitors of autophagy and a downstream target of the PI3K/AKT
targeting PI3K enzymes are being tested in this CNS pathway. Anti-cancer agents that target this pathway are
[50]
malignancy. These include the PI3K inhibitors SF1126 (a able to induce autophagy, which has a cytoprotective role as
RGDS-conjugated LY294002 prodrug) and PX-866, and well as an anti-angiogenic potential similar to the action of
the dual PI3K/mTOR inhibitor NVP-BEZ235. [28-30] These the dual PI3K-mTOR inhibitor NVP-BEZ235. [51-53]
compounds were shown to induce a substantial inhibition
of the expression of VEGF, thus reducing the invasive and High-grade gliomas have been reported to have lower
angiogenic capabilities of GBM cells. In fact, PX-866 has expression of autophagy-related proteins than low-grade
recently entered phase II studies in patients with recurrent gliomas. The amplification of EGFR, which is often
[54]
GBM. Unfortunately, preliminary results of this trial have found in these tumors, is known to suppress autophagy.
[55]
shown a low overall response rate. [31] The progression of astrocytic tumors is associated with a
decrease in autophagic capacity. In most of these CNS
[56]
The combined inhibition of VEGF and vascular endothelial malignancies, the modulation of autophagy sensitizes
growth factor receptor (VEGF/VEGFR) is currently thought tumor cells to standard chemotherapy and radiotherapy

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ March 11, 2016 ¦