PDGFRA as a potential target in H3 K27M mutant gliomas

Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq

https://www.ncbi.nlm.nih.gov/pubmed/29674595

"We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by PDGFRA signaling."

PDGFRA is a receptor tyrosine kinase (like EGFR).  No PDGFRA inhibitors have been specifically approved for brain tumors, but inhibitors have been approved for other types of cancers.  Approved PDGFRA inhibiting drugs include imatinib, nilotinib, sorafenib, and dasatinib.

ONC 201 or Avastin?

Stephen and all,
We are trying to decide between treating our son (recurrent glioma, H3 K27 mutant, mutations in ASXL 1 and PIK3CA among others) with Avastin +Irotican  or the new ONC201 trial. We tend to think that ONC201 is a better option. What do you think? Thanks!

ONC201 expanded access for H3 K27M mutant gliomas

This is rather big news for H3 K27M mutant gliomas (including a high percentage of DIPG).

Expanded Access Program for ONC201 to Treat Recurrent Histone H3 Mutant Glioma (click here)

In a phase two trial of ONC201 for recurrent GBM, a 22 year old female with secondary H3 K27M mutant GBM achieved a partial response to ONC201, which has been sustained for over 6 months. One of her two tumors regressed by 85% and the other tumor regressed by 75% after 8 and 11 months of therapy.

A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma  (click here)

Note that the H3 K27M mutation (also known as H3F3A K27M) is most common in brainstem gliomas of young children and young adults, including diffuse intrinsic pontine glioma (DIPG).  This treatment could turn out to be a breakthrough, as there is currently no known effective treatment for this tumor type.

chemo with dendritic vaccine

Dear all,
My son is finishing his second vaccine at IOZK. His tumor is astrocytoma III, H3K27m, low methylation ( our doctor still won't give us the percentage!), clean MRI ( only 4 months since surgery)
Van Gool is against any chemo for now. He wants to do another MRI in three weeks, and he added Accutane and Keytruda this time. Our US oncologist wants to do avastin and then temodar with CCNU. Another well-esteemed Russian NO who is very open- minded ( she was the one who recommended van gool to us) thinks we should continue with temodar while on vaccine since there is a good chance it worked till now. We are very confused - tend to just trust Van gool, but scared to give up chemo even for a month. Any thoughts? thank you!

Conversation with NO

Dear all,
I need some advice as to how much to share/not to share with our NO regarding my son's vaccine treatment. We just started vaccine with Van Gool  ( three weeks after the end of chemoradiation)who thinks my son should definitely not do any  chemo while on immunotherapy (except for, if we have PD1 , maybe Keytruda). He has low MGMT expression, which justifies the use of TMD, but his blood counts dropped really low the last few weeks of chemo and he generally tolerated it very poorly.  Our NO previously was talking about either doing avastin or/and maintenance or CCNU based on the post radiation MRI ( which we will have for the first time since surgery in October).
While I tend to go with Van Gool's idea, I am not sure how much I should tell our NO. I am afraid if we put it on record that my son is doing DC vaccine, that would preclude him from further clinical trials. Conversely , if we don't follow the standard procedure, maybe we could be excluded from trials as well. Our NO is a good guy ( not a brilliant professional, though), but I am not sure how much I should/should not share with him.
Thanks!

Hi Stephen,
Could I check if my interpretation of the G34r mutation of GBM is correct.
Does this mutation mean that only a small part of the tumour is methylated?

Stephen W added the following image from the study Hotspot Mutations in H3F3A
and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma

Considering treatment options for high grade diffuse midline glioma H3k27m for my 8 year old daughter

Hi all,

Thanks so much to Stephen for your in depth reply to my questions about my 8 year old daughter and invitation to this blog. We moved to Norway in July and my daughter was diagnosed in early September with high grade diffuse midline glioma with H3K27m mutation after an extended biopsy, where it was determined that the tumor was not resectable. She underwent 3 further operations to have a double valve shunt put in to relieve hydrocephalus symptoms. She finished 6 weeks of radiation and Temodal about 10 days ago. The doctors want to start her on Temodal/Lomostine 4 weeks after radiation finished. If we follow this path, we could also have a full molecular analysis done and, upon recurrence, may possibly be able to access a trial using afatinib for BI1200.120, if applicable, or another targeted agent. I would also push for using repurposed drugs in the cocktail approach if possible and our conservative doctors could be convinced. 

We are trying to explore other options, and thanks to Stephen, learned about a new phase I peptide vaccine trial opening for paediatric glioma patients with mutation H3.3K27m based in San Fransisco. It is for patients who have completed 6 weeks of radiation and have not yet started chemo again, which is exactly where we are now. https://clinicaltrials.gov/ct2/show/NCT02960230

I am finding it so difficult to determine what would be the most promising, preferably least toxic option for my daughter. Any input on how promising a peptide vaccine targeted to this kind of mutation could be? Compared with temodar/lomostine/cocktail approach?

Many thanks in advance for your input.

Jeni

mTOR inhibitors

Does anyone have any knowledge of mTOR inhibitors and availability?

I am looking into them as a target for MYCN amplification due to the
 H3F3A G34r mutation that my daughter has.

We have today had recurrence confirmed in inoperable areas and are trying to decide what may be the best way forward.
There don't seem to be a lot of options with this mutation.

Cocktail Medication Times.

I am finding it tricky to decide the best times to give my 18yr old daughter her Cocktail medications and wonder if anyone could advise?
 The NO has stopped her TMZ saying he thinks she has her first recurrence within the 6 months of  TMZ after radiotherapy. It's in a different area to original tumour and NO thinks it extends to Brain Stem so we are waiting the date of a Perfusion Sequencing MRI Scan. Her GBM is Methylated. original Biopsy said ATRX lost, focal positivity for GFAP. EMA is negative as well as IDH1. Proliferation labelled Ki67 reached 40% focally. I've been told recurrence Biopsy if done would probably have different results.
I am keen therefore to get the maximum benefit from the medications she is on, which are:-
Celebrex 100mg x 2  x twice daily
Itraconazole 100mg x 1 x once a day
Keppra 750mg morning 1000mg evening
Metformin 500mg x 1 x twice daily
Omeprazole 20mg x1 x twice daily
Rantidine 150mg x1 x once a day
Dexamethasone 6mg x twice daily
Melatonin 10mg x 2 bedtime
Docusate 100mg if required for constipation.
Cyclizine 50mg x 1 up to 3 times daily if required for nausea.
PSK 16 1070mg x 3 once daily
Pure Fish Oil 1100mg x 2 once daily
Vitamin D3 x 2 1000unit tabs once daily.
Yesterday she also started Doxycycline 100mg x 1 once a day.
I read that Dexamethasone reduces the effectiveness of Itraconazole and some medications like
Doxycycline need to be taken two hours apart from indigestion remedies.
Any help as to how to optimize the use of these medications, and /or any recommended treatment advice would be greatly appreciated.
I'm aware that she needs to be on more Cocktail medications but these are proving difficult to get at the moment. Not sure if there any that would be of particular benefit to get right now?We are awaiting delivery of Boswellia and are hoping to get a prescription for Low Dose Naltrexone.
Regards
Jo

IDH1/IDH2 status?

I've spent some time on the sister site, AstrocytomaOptions, but I'm still not quite sure of the significance of these two markers.

My wife doesn't appear to have either of these mutations and I'm not sure if that's a good or bad thing, or is it merely a status. Does someone that doesn't have these mutations change their cocktails, and if so, in what meaningful way?

Thoughts?