Glioblastoma (GBM) is the deadliest form of brain cancer, and despite decades of effort, survival rates have barely improved. While we’ve learned a lot about cancer pathways, glioblastoma remains particularly elusive because of its complex, tangled web of signaling networks. New research has revealed how major pathways like PI3K, MAPK, and cAMP interact and offer potential new targets for therapy. Therefore, understanding these pathways could be the key to finally outsmarting this brutal disease.
Why Glioblastoma Matters
GBM isn’t just another cancer—it’s an aggressive, invasive, and heterogeneous beast. After initial surgery, chemotherapy (typically temozolomide), and radiation, tumors almost always return within months. Median survival is just 14 months, with a 5-year survival rate of less than 5%[1].
What the Science Shows Us
The article, Understanding and Exploiting Cell Signalling Convergence Nodes and Pathway Cross-Talk in Malignant Brain Cancer, explores three crucial pathways:
- PI3K pathway: Promotes cell survival, proliferation, and invasion. Mutations in genes like PTEN often hyperactivate this pathway in GBM.
- MAPK pathway: Drives cell division and survival. EGFR mutations, common in GBM, turbocharge this cascade.
Figure 1 [1] - cAMP pathway: Normally suppresses tumor growth, but GBM often has abnormally low cAMP activity.
Each of these pathways individually promotes tumor growth.. PI3K and MAPK can activate each other, bypassing single-drug therapies. Meanwhile, cAMP can suppress parts of MAPK and PI3K, offering a potential therapeutic counterbalance.
How This Could Change Treatment
Glioblastoma (GBM) is hard to treat because it can quickly find new ways to grow when one path is blocked. It’s like cutting off one road, only to have the tumor take a different route. That’s why treating just one pathway at a time often doesn’t work for long. But new research suggests smarter ways to attack the tumor:
Combining Treatments
- Instead of blocking just one pathway, scientists are now trying to block two or more at the same time, like PI3K and MAPK. These pathways often work together, so stopping both may prevent the tumor from finding a new route to grow [2].
Targeting Key Hubs
- Some proteins, like CREB, sit at the center of many important growth signals. By targeting CREB, we could shut down several tumor pathways at once. This might make it harder for the tumor to adapt and could also target the cells that help tumors grow back [1,3].
Restoring Natural “Off” Signals
- Healthy brain cells use cAMP signaling to control growth and trigger cell death. GBM cells often shut this down. Some drugs can boost cAMP, pushing the cancer cells back toward normal behavior or even killing them. But if MAPK is too active, the tumor resists this effect, so blocking MAPK at the same time could make these drugs work better [4].
So Why Should the Public Care?
Glioblastoma is deadly because it quickly adapts to treatments by switching between different growth pathways. These new strategies focus on combining therapies, targeting key control points like CREB, and restoring natural tumor-blocking signals like cAMP.
By attacking multiple weak spots at once, we could finally slow tumor growth, prevent resistance, and improve survival. Instead of reacting to the tumor’s changes, we could stay one step ahead.
[1] Fung NH, Grima CA, Widodo SS, Kaye AH, Whitehead CA, Stylli SS, Mantamadiotis T. Understanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer. Cell Signal. 2019 May;57:2-9. doi: 10.1016/j.cellsig.2019.01.011. Epub 2019 Jan 30. PMID: 30710631.
[2]Julien, L. A., Carriere, A., Moreau, J., & Roux, P. P. (2010). mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Molecular and cellular biology, 30(4), 908–921. https://doi.org/10.1128/MCB.00601-09
[3] Mantamadiotis T, Papalexis N, Dworkin S. CREB signalling in neural stem/progenitor cells: recent developments and the implications for brain tumour biology. Bioessays. 2012 Apr;34(4):293-300. doi: 10.1002/bies.201100133. Epub 2012 Feb 13. PMID: 22331586.
[4] Daniel PM, Filiz G, Mantamadiotis T. Sensitivity of GBM cells to cAMP agonist-mediated apoptosis correlates with CD44 expression and agonist resistance with MAPK signaling. Cell Death Dis. 2016 Dec 1;7(12):e2494. doi: 10.1038/cddis.2016.393. PMID: 27906173; PMCID: PMC5261024.
