All,
We did tumor genetic test at UCSF. Here's the mutations they found...
Please let me know your insights and suggestions for what medicines or therapies are more vs. less effective given these genetic mutations. Mom's radiation is over now and we are planning the next steps. What FDA-approved as well as experimental drug should I push for? thx
We did tumor genetic test at UCSF. Here's the mutations they found...
Please let me know your insights and suggestions for what medicines or therapies are more vs. less effective given these genetic mutations. Mom's radiation is over now and we are planning the next steps. What FDA-approved as well as experimental drug should I push for? thx
The TERT promoter mutation is the most common mutation in GBM (occurring in 80-90% of all cases), though is not "actionable" or druggable with currently available drugs.
ReplyDeleteCDKN2A/2B deletion is another of the most common alterations in GBM, especially in the "classical" subtype. CDKN2A/B is a "cyclin dependent kinase inhibitor" that inhibits cyclin dependent kinases CDK4 and CDK6. These cyclin-dependent kinases, in co-operation with cyclins, promote the cells progression through the cell cycle (that is cell division). There is a CDK4/6 inhibitor drug called palbociclib approved for breast cancer in 2015, but as with all new oncology drugs is very expensive, and its use in GBM is uncertain (blood-brain barrier penetration is always a major question mark).
PTEN is another tumor suppressor protein that counteracts PI3K. Mutations in this gene are usually deactivating, leading to overactivation of the PI3K/Akt/mTOR pathway. There are PI3K and Akt inhibitors currently in trial, and rapamycin (sirolimus) and other "rapalogs" like everolimus and temsirolimus can inhibit mTOR complex 1, but these have not been that successful to date in GBM trials. A recent mouse study shows the anti-hypertension drug called prazosin can inhibit Akt expression.
http://www.ncbi.nlm.nih.gov/pubmed/27138566
EGFR amplification and EGFRvIII mutation are also trademarks of the classical subtype of GBM. These are probably the most actionable of all the mutations found. There are a number of EGFR inhibitors approved for other cancers (eg lung cancer), but the usual problems of blood-brain barrier penetration apply here. Chloroquine plus chemo may be more effective in EGFRvIII tumors than other types.
There are also several trials targeting EGFRvIII. The rindopepimut phase 3 trial failed to meet its endpoint, but some may still be able to get this on compassionate use perhaps?
http://astrocytomaoptions.com/currently-recruiting-trials-high-grade-glioma/
https://www.clinicaltrials.gov/ct2/show/NCT02303678
https://clinicaltrials.gov/ct2/show/NCT01967758
"Targeted" therapy directed towards specific signaling pathways is not always the most effective therapy. I'm most excited about various immune and viral therapies.