Hi All,
My Dad was diagnosed with a GBM in October 2016 and has since had chemoradiation, on his 5th TMZ cycle, and has had two Avastin infusions.
The Avastin infusions immediately cleared up his MRIs (the inflammation, not the tumor) and have allowed us to taper his decadron from 4mg/day to 2.5mg/day, but we know that Avastin is not the long term answer so I am preparing for our next step.
As I'm sure everyone is, I'm pushing to have a better than standard of care "newly diagnosed stage" plan (which is right now), as well as a plan for if/when we hit the "recurrent stage".
My last post mentioned our NO's interest in Abemaciclib and the possibility of getting compassionate use, but since then our NO was at a Brain Tumor Conference in Zurich, Switzerland (Lilly, the drug manufacturer of Abemaciclib was there) and did not receive any promising results or information to keep us pursuing this path.
Our next plan is to look at PARP Inhibitors. An article and strategy that quickly caught my families attention is about the combination of SAHA (an HDAC class I + II inhibitor) and Olaparib (a PARP inhibitor).
See the following article below:
https://www.ncbi.nlm.nih.gov/pubmed/26794465
and for full article see this link:
http://onlinelibrary.wiley.com/doi/10.1016/j.molonc.2015.12.014/full
A previous post on this blog mentioned Rucaparib (another PARP inhibitor) has been shown to not penetrate the blood brain barrier effectively, but has anyone heard specific results about oliparib?
Both Olaparib and SAHA are being tested individually in currently active clinical trials with TMZ but I have not been able to find any of the results.
One caution our NO mentioned was that PARP inhibitors can cause issues with blood counts, especially for someone who is on TMZ cycles.
Would love to hear what you all think about this plan and whether you have heard the good/bad/ugly on the PARP Inhibitor trials I mentioned about.
Amazing community we have here. Thank you all for the time.
Ari
Oakland, CA
Vorinostat (SAHA) penetrates the brain poorly, with mouse studies showing a free brain-to-plasma ratio of 0.01.
ReplyDeleteSAHA Enhances Synaptic Function and Plasticity In Vitro but Has Limited Brain Availability In Vivo and Does Not Impact Cognition
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724849/
Rucaparib and olaparib also both have challenges, both being substrates of the drug efflux pump P-glycoprotein, abundantly expressed at the blood-brain barrier.
Currently the best candidate PARP inhibitor for brain tumors is likely BGB-290, a brain penetrant PARP inhibitor in clinical trial in Australia:
https://clinicaltrials.gov/ct2/show/NCT02361723
https://clinicaltrials.gov/ct2/show/NCT02660034
Like veliparib, another PARP inhibitor in trial for brain tumors, BGB-290 has "significant brain penetration". Unlike veliparib, BGB-290 has potent "PARP-trapping" ability which correlates well with the cytotoxicity of PARP inhibitors, especially in combination with temozolomide. Velaparib is actually the weakest PARP trapper of all PARP inhibitors in clinical development.
http://www.beigene.com/pipeline/clinical-candidates/bgb-290/
Laying a trap to kill cancer cells: PARP inhibitors and
their mechanisms of action
http://stm.sciencemag.org/content/8/362/362ps17
Regarding blood toxicity, this will indeed likely be the dose-limiting toxicity in combining PARP inhibitors with temozolomide. From the above review:
"Although the initial phase 1 study
suggested that full-dose temozolomide could
be administered with low-dose rucaparib, a
further phase 2 evaluation of this combina-
tion in patients suffering from metastatic
melanoma revealed that myelosuppression
was a major challenge to the administration
of this combination"
"This has been recapitulated by other cytotoxic and PARP inhibitor combination trials; overall, these studies
indicate that administering tolerable doses
of these combinations requires truncated PARP
inhibitor schedules."
The combination of PARP inhibitors with high PARP-trapping activity with TMZ is worth pursuing in clinical trials however, because it can sensitize TMZ-resistant tumors to TMZ in an MGMT independent manner, potentially making an effective combination therapy for MGMT-unmethylated tumors. The maximum tolerated dosing and best drug scheduling has yet to be worked out, as mentioned in the quote above.
Thanks for the response Stephen. We are looking into BGB-290 this weekend.
ReplyDeleteYou mention: "Rucaparib and olaparib also both have challenges, both being substrates of the drug efflux pump P-glycoprotein, abundantly expressed at the blood-brain barrier."
Of course I then found the following articles that all seem to push that Olaparib does penetrate the BBB at therapeutic levels or at the very least sensitizes cells to TMZ.
Is the problem with these studies below (all three are from 2014) the fact that they are all pre-clinical, and although showed promise in test tubes and mice... have not shown promise penetrating BBB in humans?
Just want to make sure I'm not missing anything.
http://conference.ncri.org.uk/abstracts/2014/abstracts/para52.html
http://ascopubs.org/doi/abs/10.1200/jco.2014.32.15_suppl.2025
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114583#pone.0114583-Allen1