Replies to post #64640 on NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

Excuse me for all the cut and paste, but it is shorthand for elucidating partial answers to your questions. I would not do any of this justice if I put it in my own words.

Glioblastomas (GBMs) are the most common and malignant central nervous system (CNS) neoplasms and arise initially as grade 4 tumors (primary GBM) or evolve from lower grade gliomas (secondary GBM). Deep molecular analyses of primary GBMs have divided them into four classes denoted proneural (PN), mesenchymal (MES), classical (CL), and neural (NL) (Brennan et al., 2009; Phillips et al., 2006; Verhaak et al., 2010). However, in some cases the division is blurred in that a sample might show patterns of more than one subtype (Brennan et al., 2009; Phillips et al., 2006; Sottoriva et al., 2013; Verhaak et al., 2010). These subclasses can be associated with canonical mutations such as PDGFRA amplification in PN-GBM, loss of NF1 in MES-GBM, and amplification of EGFR in CL-GBM. In the case of NL-GBMs, particular molecular abnormalities remain unidentified.

One of the best-studied GBM subclasses is PN-GBM, some of which carrying mutant IDH1 or IDH2 and have the methylator phenotype denoted by GCIMP (Noushmehr et al., 2010). Although the transcriptomal patterns for GCIMP tumors resemble those of the other PN-GBMs (non-GCIMP), their biology is significantly different in that the GCIMP GBMs display global hypermethylation of CpG islands, characteristic copy number alterations, and prolonged patient survival, suggesting that these tumors represent high-grade versions of grade 2 and 3 diffuse gliomas, which are commonly GCIMP, and thus represent secondary GBMs (Noushmehr et al., 2010; Ohgaki and Kleihues, 2012).

The existence of different GBM subtypes raises questions regarding their natural history and the temporal sequence in which individual alterations arise (Bhat et al., 2013; Phillips et al., 2006; Sottoriva et al., 2013). Furthermore, it is unclear whether these subgroups are fundamentally different tumors from their inception, or whether they evolve from a common glioma precursor.

Given the evidence of spontaneous conversion of human PN to MES tumors and observed subtype mosaicism within the same tumor (Phillips et al., 2006; Sottoriva et al., 2013), the GBM subtypes might be directionally variable from one subtype to another. Finally, it remains unclear whether the existence of subgroups has therapeutic implications (Bhat et al., 2013). For example, the subtype-defining mutations may be promising therapeutic targets if they represent initiating genetic events in glioma evolution but their inhibition would unlikely provide lasting therapeutic benefit if they represent late events. -- www.ncbi.nlm.nih.gov/pmc/articles/PMC4143139/