2 days ago a study about olaparib and IDH mutant gliomas appeared. Since olaparib is already an approved PARP inhibitor for treatment of ovarian cancer and trial for gliomas in the end of 2017 is expected, I thought someone might find it useful.
"The researchers tested several existing cancer drugs on the mutated cell lines. They found that tumor cells with the mutant genes were particularly sensitive to a drug, olaparib, recently approved for the treatment of hereditary ovarian cancer. The drug caused a 50-fold increase in brain tumor cell death."
https://www.sciencedaily.com/releases/2017/02/170202141211.htm
And link to the study:
2-Hydroxyglutarate produced by neomorphic
IDH mutations suppresses homologous recombination and induces PARP
inhibitor sensitivity
http://stm.sciencemag.org/content/9/375/eaal2463 Also I did a quick search for olaparib and glioma and there are already trials with olaparib and TMZ for recurrent GBM.
This was a fascinating study, and I'm planning to do an Astrocytoma Options update on it. My main question in all of this is: does olaparib (or rucaparib, a second PARP inhibitor approved by the FDA just over a month ago) cross into the brain in therapeutically effective quantities? It was very interesting that the IDHmut subcutaneous xenograft mouse model in this study was responsive to olaparib, but the isogenic IDH wild-type model was unresponsive. Current or future trials testing PARP inhibitors for glioma should really pay attention to IDH1 status.
ReplyDeleteI've just updated the Exploring Strategies for IDH1 Mutated Gliomas page at Astrocytoma Options with a summary of the new study. The summary is found at the top of the page.
ReplyDeletehttp://astrocytomaoptions.com/exploring-strategies-for-idh1-mutated-gliomas/
Nice summary :)
ReplyDeleteI did a quick search on olaparib and blood brain barrier, this presenatation came up:
PARP inhibitors and TEMOZOLAMIDE in BRAIN TUMORS
http://www.geino.es/wp-content/uploads/Symposium2015/Ponencia_InhibidoresPARP_Dra_MORILLA.pdf
Where there are some conclusions from OPARATIC trial (olaparib+TMZ for rGBM):
"Olaparib detected in 24/24 recurrent GBM specimens.
Mean tumour concentrations in same range as those observed in previous breast cancer study (1).
Tumour olaparib concentrations did not correlate with olaparib dose or plasma concentrations.
100 mg once daily oral dosing delivered tumour concentrations associated with clinical responses (1)"
And also "Olaparib is a substrate for MDR1 and does not cross the intact BBB under normal conditions."
So to summarize, I guess olaparib gets to the tumor, if blood brain barrier is already disrupted (contrast enhancement on MRI)
Thanks Matjaz, I came to the same conclusion - that olaparib would probably not be as effective in lower grade tumors with little disruption of the blood-brain barrier, unless an effective inhibitor of MDR1 (P-glycoprotein) was also used to temporarily disable the drug efflux pump at the blood-brain barrier.
DeleteSee also:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674360/
"Efficacy of PARP inhibitor rucaparib in orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system"
hello Matjaz,
DeleteI have a question to you:
how long did you get TMZ prescribed?
because my husband is on 24 month taken after radiation.
and I want to know if is anybody who is on same situation.
thank you ,
Melinda Voicu
Hi Melinda,
DeleteI am on my 26th cycle of TMZ. I have had a very well respected NO tell me to go a few more cycles and another very respected NO tell me that I should definitely stop now due to the risks associated with long term TMZ. There is no clear answer.
In the latest Ben Williams update a Japanese study concluded that 12 cycles of TMZ were better than 6, but that 24 cycles were no better than 12. I don't think there is much information on going beyond 24 cycles.
Mike B
Hi Mike,
Deletethank you for your input, I appreciate your opinion, yes we also going for more cycle of tmz , if our oncologist agree, I don't know yet, but we wish to continue. I will keep you all posted.
Melinda.
Hello Melinda,
Deletesince I had complete resection of low grade oligodendroglioma, no chemotherapy was given to me at this time.
sorry Matjaz,
DeleteI don't know why i supposed you have GBM,
I wish you good health and get well.
Melinda
No problem melinda. I think oligodendroglioma is rather rare brain tumor.
DeleteI wish you and your husband good health as well!
I had some time waiting at the dentist and I found this:
ReplyDeleteThe PARP inhibitor, niraparib, crosses the blood brain barrier in rodents and is efficacious in a BRCA2-mutant intracranial tumor model
http://mct.aacrjournals.org/content/14/12_Supplement_2/B168
I'm really spamming this thread, but another useful study on this matter:
DeletePoly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma.
https://www.ncbi.nlm.nih.gov/pubmed/26351319
The niraparib study is interesting. The drug hasn't been approved yet, but is being fast-tracked so likely will be soon.
DeleteYou've never spammed this blog Matjaz, the intention of spam is to sell a product, not to inform. Thanks for the links.
DeleteI'm curious to see if used with resection and chemoradiotherapy if that could help increase efficacy for LGG since radiotherapy comprises the BBB.
ReplyDeleteA second study showing PARP inhibitors can improve response in IDH1 mutant cells
ReplyDeletehttp://cancerres.aacrjournals.org/content/early/2017/02/15/0008-5472.CAN-16-2773
"Chemosensitivity of IDH1 mutant gliomas due to an impairment in PARP1-mediated DNA repair"
This was only an in vitro study, whereas the Yale study I summarized on Astrocytoma Options also validated their findings in vivo.
DeleteNew studies unravel mysteries of how PARP enzymes work
ReplyDeletehttps://www.sciencedaily.com/releases/2017/02/170217012511.htm
Link to the article in the bottom.
To be honest I didn't read whole study, just the summary on ScienceDaily.
"The second study reports how PARP-1 regulates embryonic stem cell self-renewal and pluripotency (ability to become different cell types), but without using its enzymatic activity. Instead, in this case, PARP-1 functions as a structural component of chromosomes in the nucleus, creating binding sites for the critical embryonic stem cell transcription factor Sox2. This action allows transcription of genes necessary to maintain the ability of embryonic stem cells to continue self-renewing, rather than becoming a specific cell type, the research shows."
But if I understand correctly PARP inhibitors would be viable option against glioma stem cells, since SOX2 is associated with CSCs?
At the moment I'm considering the use of Olaparib and collect all information about possible dosages and schedules.
ReplyDeleteSNO 2017, OPARATIC trial
http://www.practiceupdate.com/content/sno-2017-olaparib-looks-promising-in-combination-with-temozolomide-in-relapsed-glioblastoma-and-is-well-tolerated-in-combination-with-short-course-radiation-in-elderly-patients-with-newly-diagnosed-disease/60787/13/1/2?usersourceid=2287&trendmd-shared=1
"The expansion cohort dose was defined as temozolomide 75mg/m2 of body surface area daily + olaparib 150 mg once daily on days 1 - 3 weekly. In the expansion cohort, nine of 13 patients completed cycle 1, two of 13 completed cycle 2, and two of 13 completed cycle 3."
I did not quite understand the information about the cycles in this trial.
1 cycle = 1 week?
This means that the maximum duration of taking Olaparib was 3 weeks (on days 1-3 of each week) ???
2017-2018 https://clinicaltrials.gov/ct2/show/NCT03212742
In this open-label study, for example, such a dose is proposed in combination with radiation therapy and temozolomide:
"We propose 7 dose levels to reach the target dose of 400 mg per day (200 mg twice daily) of olaparib continuously DL1 (starting dose level) : Olaparib 50 mg Q12H Monday to wednesday DL2 : Olaparib 100mg Q12H Monday to wednesday DL3: Olaparib 100mg Q12H Monday to friday DL4 : Olaparib 200mg Q12H Monday to wednesday DL5: Olaparib 200mg Q12H Monday to friday DL6: Olaparib 200mg Q12H, continously."
Have you seen other information about the doses / schedules of Olaparib in the trials for glioblastoma?
I think a cycle in the OPARATIC trial is considered to be 8 weeks: 42 days of TMZ (6 weeks), plus a two week break.
Delete"After recovery from surgery, patients receive oral olaparib once or twice daily and oral temozolomide once daily on days 1-42. Treatment repeats every 8 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity."
Olaparib given on days 1-3 each week. Olaparib on days 1-5 per week in the OPARATIC trial was apparently too myelosuppressive so was reduced to day 1-3 every week.
A much simpler schedule is used when olaparib is given alone: twice daily every day of a 28 day schedule.
https://clinicaltrials.gov/ct2/show/NCT03212274
More details on OPARATIC trial here:
Deletehttps://clinicaltrials.gov/ct2/show/NCT01390571
They don't call it "OPARATIC" in this clinicaltrials.gov entry, but according to this ASCO abstract it is the same trial.
https://meetinglibrary.asco.org/record/146706/abstract
Stephen, thanks a lot for your help!
DeleteIn the end, I consider adding an olaparib to our cocktail on days 1-3 of each week for 100-150 mg. I'm afraid that as a single agent the olaparib will not work and probably it needs to be added while there is an effect from Avastin + Lomustin.
Unfortunately, I'm not a doctor, and not even a nurse. I am a lawyer. But I have to make decisions, because the standard decision of doctors is just a few standard drugs without any hope. I have to decide something and this is a big responsibility, and it's terrible.
By the way, strangely, in this study, one of the conditions for participation is the presence of IDH1/2 mutations.
https://clinicaltrials.gov/ct2/show/NCT03212274
"Patients with previously identified IDH1/2 mutations can be enrolled on the trial, but must be verified in the central study laboratory"
And there are no conditions for PTEN.
This trial is being run at Yale by Ranjit Bindra, whose lab identified sensitivity to PARP inhibitors in IDH1 mutant gliomas.
Deletehttps://www.ncbi.nlm.nih.gov/pubmed/28148839
So that is the hypothesis they're testing in this particular trial.