Hello all,
I found this trial in Europe (Heidelberg Germany):
https://clinicaltrials.gov/show/NCT02718443
http://abstracts.asco.org/199/AbstView_199_191829.html
What's your opinion, does it seem something that could work on recurrent AA3 (IDH1 mutated, MGMT methylated) (ASCO abstract goes beyond my understanding... :)
Or would it be better to go with PARP + TMZ combo?
br,
Juha
Looking at mRNA data, G-CIMP positive gliomas (read IDH1 mutant) have a greatly reduced expression of VEGF-A and greatly increased expression of VEGF-B versus non-GCIMP gliomas (mostly GBM). The receptor VEGFR1 (gene name FLT1) is a receptor for VEGF-A as well as VEGF-B. The receptor VEGFR2 (gene name KDR) that this vaccine is targeting, is a receptor for VEGF-A, but not VEGF-B.
ReplyDeleteBased on this data, I would expect this vaccine to be less effective for IDH1-mutant gliomas compared to IDH wild-type GBM, and that the VEGF-B/VEGFR1 signaling axis might be a better target for IDH1-mutant gliomas. In support of one half of this conclusion, Avastin, which is an antibody against VEGF-A, has a poor track record for low grade gliomas (the majority of which are IDH1-mutant) and in the TAVAREC clinical trial, Avastin did not improve progression-free survival nor overall survival for grade 2 and 3 astrocytoma patients.
Again in terms of mRNA expression, PDGFRA is the most highly expressed receptor tyrosine kinase in G-CIMP positive gliomas, whereas EGFR is more highly expressed in non-G-CIMP (IDH non-mutant) glioblastoma.
I would go with the TMZ + olaparib (+ disulfiram/copper + long-chain omega 3 fish oils).
Alternatively, if I were pursuing immunotherapy for IDHmutant glioma I would attempt to combine it with one of the mutant IDH1 inhibitor drugs (if I could get it on compassionate use). The reason being that 2-hydroxyglutarate (produced by mutant IDH1) causes immunosuppression in the tumor environment.
I would not combine mutant IDH1 inhibitors with the TMZ + olaparib cytotoxic strategy, as 2-hydroxyglutarate sensitizes the tumor to many of these cytotoxic therapies, and is one of the reasons mutant IDH1 gliomas have a better prognosis and are more responsive to conventional therapies.
Thanks Stephen!
ReplyDeleteWe'll meet my sister's neurosurgeon in couple of weeks and we'll discuss with oncologist again after that. I'll let you know how it goes.
br,
Juha
Hey guys,
ReplyDeletehow about that Toca trial, which showed some good results on IDH1mut?
Take care!
Hello Matjaz!
ReplyDeleteToca 511 + Toca FC is something I hope will succeed and get FDA (+ EU) approval fast.
To my understanding the trial is not currently recruiting:
https://clinicaltrials.gov/ct2/show/NCT02414165
thanks anyway!
br,
Juha