NorthWest Biotherapeutics Inc (NWBO)

[abeta]

I'm out of my depth here - but these articles support what you wrote
and I may have missed important insights into them esp G-CIMP

The Somatic Genomic Landscape of Glioblastoma
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Cluster M1 (35/58, 60%) is enriched for mesenchymal GBMs

while cluster M3 (18/31, 58%) is enriched for classical subtype

As expected, the G-CIMP cluster is enriched for proneural subtype tumors.

In summary, our data provides evidence for MGMT DNA methylation as a predictive
biomarker in the GBM Classical subtype of GBM, but not other subtypes.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910500/#SD3


The landscape of the mesenchymal signature in brain tumours
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Using gene expression and DNA methylation profiles, Brennan et al. (2013) classified 396 GBMs
into six methylation groups [clusters M1, M2, M3, M4, glioma CpG island methylator phenotype (G-CIMP), and M6].

The mesenchymal subtype was enriched in the M1 cluster (60%) and classical in the M3 cluster (58%),
while the G-CIMP cluster contained mainly the proneural subtype and was associated
with somatic mutations (IDH1, TP53, ATRX, MYC).

(I just realized that both authors MUST be referencing the SAME SOURCE.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485274/

The Somatic Genomic Landscape of Glioblastoma
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Cluster M1 (35/58, 60%) is enriched for mesenchymal GBMs while cluster M3 (18/31, 58%) is
enriched for classical subtype (Figure 5B, red and blue, respectively).
As expected, the G-CIMP cluster is enriched for proneural subtype tumors.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910500/#SD3


Molecular differences in IDH wildtype glioblastoma according to MGMT promoter methylation
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We identified 3 methylation clusters.

Cluster 1

showed the highest average methylation and was enriched for mMGMT tumors.
Seventeen genes including gastrulation brain homeobox 2 (GBX2) were found to be hypermethylated and
downregulated on the mRNA level in mMGMT tumors.
In progressive glioblastomas, platelet derived growth factor receptor alpha (PDGFRA) and GLI2
amplifications were enriched in mMGMT tumors.

Methylated MGMT tumors gain PDGFRA amplification of PDGFRA, whereas uMGMT tumors with amplified PDGFRA frequently
lose this amplification upon progression.

Glioblastoma patients surviving <6 months and with mMGMT harbored less frequent epidermal growth factor receptor (EGFR) amplifications,
more frequent TP53 mutations, and a higher tumor necrosis factor–nuclear factor-kappaB (TNF-NF?B)
pathway activation compared with patients surviving >12 months.

Methylated MGMT tumors were

overrepresented in cluster 1 (44% vs 31%, P = 0.0001) and

underrepresented in cluster 3 (28% vs 40%, P = 0.0001; Fig. 3E).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817966/


Dr Linda Liau - 2019/2018
Correlation of commercially available quantitative MGMT (O-6-methylguanine-DNA methyltransferase)
promoter methylation scores and GBM patient survival
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using a threshold of 2 to distinguish MGMT methylated from unmethylated tumors.
we sought to determine whether the magnitude of the methylation score correlated with outcome.
Contrary to our expectation, when we substratified the ≥2 (methylated) group, we did not find a
dose-dependent relationship between the magnitude of MGMT methylation and improved survival.

Conclusions
The MGMT unmethylated group contains a partially methylated group (greater than 1)
that shares survival benefits similar to the methylated group

I am wondering did the trial MOTIVATE her to look into mMGMT more closely