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Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center Rotterdam, the Netherlands ? or a A

Transcript of Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent...

Page 1: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

Glioblastoma pathophysiology:

M.J. van den BentThe Brain Tumor Center at Erasmus MC Cancer Center

Rotterdam, the Netherlands

?or aA

Page 2: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

Pathophysiology: pathophysiology seeks to explain the physiological processes or mechanisms whereby such condition develops and progresses

Pathophysiology, glioblastoma & Pubmed: 1174 hits, incl

Targeting NF-κB in glioblastoma: A therapeutic approach

JC polyomavirus in the aetiology and pathophysiology of glial tumours

Role of Nitric Oxide in Glioblastoma Therapy: Another Step to Resolve the Terrible Puzzle ?

The role of ion channels in malignant brain tumors.

MicroRNA-1908 functions as a glioblastoma oncogene by suppressing PTEN tumor suppressor pathway.

CRMP5 Controls Glioblastoma Cell Proliferation and Survival through Notch-Dependent Signaling.

The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma.

Intersectin1-S, a multidomain adapter protein, is essential for malignant glioma proliferation.

Page 3: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

Cancer: bad luck or environment?

“Variation in cancer risk among tissues can be explained by the number of stem cell divisions”: Most Cancers Caused By Bad Luck?

Tomasetti, Vogelstein: stem cell divisions correlate with life time risk on cancer. Cancer due to randome mutations in 22:31 cancertypes?1

Wu et al: rates of endogenous mutation accumulation by intrinsicprocesses are not sufficient to account for observed cancer risks2

Intrinsicprocesses

Extrinsicfactors

Stem-celldivision

Cancerrisk

1Tomasetti et al Science 2015;347:78-81; 2Wu et al, Nature 2016;529:43-48

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Hereditary syndromes and glioblastoma

Li fraumeni: TP53 mutation: breast cancer, sarcoma, glioblastoma

Turcot syndrome: mutations in mismatch repair genes (MSH6): polyposis coli, colorectal cancer, glioblastoma

Cowden disease: PTEN mutations: Cancers, Lhermitte Duclos(cerebellar gangliocytoma)

NF1: neurofibroma, glioma incl glioblastoma

Environment factors and glioblastoma Ionizing radiation

The observed stability of brain cancer incidence in Australia between 1982 and 2012 (…) suggests that the observed increases in brain cancer incidence in the older age group are unlikely to be related to mobile phone use Chapman et al, Cancer Epidemiology, May 5 2016, http://dx.doi.org/10.1016/j.canep.2016.04.010

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Chain of events:

Precursorcell

1st hit

Driver vs passenger mutationsClonal vs subclonal

Changes in the micro-environnementEssential vs non-essential

Glioma stem cell

Autocrine/paracrinestimulation

Alterations in intracellularsignaling/pathways

Clonal expansions

Changes in themicroenvironnement

Clinical relevance: potential therapeutic targets

Page 6: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

The cancer stem cell and subclonalexpansion: no linear connection…

Page 7: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

TCGA: The Somatic Genomic Landscape of Glioblastoma

M14-483 Investigator Meeting | 18 September

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Brennan, et al. Cell. 2013;155:462–477.

Page 8: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

The TCGA effort: major improvement of theunderstanding of the complexity of this disease

Most glioblastoma are characterized by mutational hits in three major pathways: PI3K pathway, Rb pathway, p53 pathway

However: at a multitude of different levels, mutuallyexclusive (e.g., either PTEN mutation/deletion or PI3K mutation)

“Another level of biological complexity is revealed by targeted proteomic profile, which showed that the impact of specific genomic alterations on downstream pathway signaling is not linear and not always predictably concordant with genotype”

Brennan, et al. Cell. 2013;155:462–477.

Page 9: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

Rb and p53

Page 10: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

Altered cell signalling and hallmarks of cancer: EGFR

Page 11: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

The hallmark of cancer: six biological capabilities aquired during themultistep development of human tumors.

In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the ‘‘tumor microenvironment.’’

Hanahan, Weinberg Cell 2012

Page 12: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

Signalling Interactions in the Tumour Microenvironment During Malignant Progression

12Hanahan D, Weinberg RA. Cell. 2011;144:646-674.

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The microenvironment: another glioblastoma target?

Several microenvironmental changes have been used as targets:

Inhibition of angiogenesis (bevacizumab, cediranib)

Inhibition of integrines (cilengitide)

Immunotherapy (rindopepimut, vaccination strategies, PD1 antibodies)

Inhibition of matrixmetalloproteinases

Page 14: Glioblastoma pathophysiology - lgksociety.com · Glioblastoma pathophysiology: M.J. van den Bent The Brain Tumor Center at Erasmus MC Cancer Center. Rotterdam, the Netherlands. A.

Immunotherapy and tumors: the immune suppressive tumor

cancer cell

T regulatorycell

Tumor fragments: proteins

T effector cell

Antigen Presenting Cell

Stimulate APC + Vaccination

Stumulate earlyT-cell activation

Dendritic cell

Immune system:Checks and balances

MHC class receptors

Co-stimulatory factors TNF-α, IL1, CD40L/CD40

Immune system

PD-L1/PD1TGF-β, VEGF

Remove T-effinhibition (anti-PD1)

CTLA4CD27/CD70

IL10

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Glioblastoma, a gordian knot?

Jean-Simon Berthèlemy: Alexander cutting the Gordian Knot