Sunday 31 March 2019

Irina's mom genomic sequencing report

Dear Stephen! Dear all!

1) Could you please help me with genomic sequencing report!
Probably you could advice any beneficial drugs for our sitation.
Now we use DCA, metformine, chloroquine, celebrex, prozak, boswellia, pterostilbene, EGCG, BroccoMax, berberine, omega 3, milk thistle, cannabioids with high thc - 74%).












Options 1 and 3 have the most pathological nature.
  • Option number 1 is located in the KDR gene, which is an oncogene, and involved in tumor angiogenesis processes.
  • Option number 3 is in the gene PMS2, which belongs to the tumor suppressor genomes, and is involved in the repair of unpaired
  • bases (edits DNA replication errors). Associated with many tumor diseases. This option, as follows from sources (column PMID) often has a germinal nature (is congenital).
  • Option number 4 is located in the gene ROS1, which is a proto-oncogene, and encodes a number of tyrosine kinase receptors. He might be both congenital and acquired. 
These mutations currently have no targeted drugs.

Mutation load (Tmb) - high: 3.79 m/Mb (with a threshold value of 0.8 m/Mb)
Microsatellite instability (MSI) - presence (bottom line):
- 11.9% / 12% repeat
- mutations 2 reparation genes of 4

2) How do you think is it worth to try ONK201 drug for my mom if she don't have h3k27m mutation? I read on the forum on face book that many adults with glioblastoma without mutation use it and have positive results. 
Does it really kill tumor stem cells?


Thank you so much!

22 comments:

  1. Here in this case, a checkpoint inhibitor can be considered.

    ReplyDelete
  2. Which company/institution did this sequencing and how many genes were sequenced?

    They must have used different methods for determining TMB compared to companies like FoundationOne, because usually ~ 5 or less mutations per Mb is about average, and over 20 mutations per Mb is considered high TMB.

    No drugs come immediately to mind for these specific mutations, as you say there no approved drugs that specifically target them. If TMB is really elevated, with microsatellite instability, then treatment with immune checkpoint inhibitors such as pembrolizumab and nivolumab has a chance of being effective. I would also ask if it would be possible to do an immunohistochemical test for PD-L1 expression in the tumor. If elevated, this would provide additional rationale for using PD-1 or PD-L1 checkpoint inhibitors.

    http://clincancerres.aacrjournals.org/content/early/2018/12/19/1078-0432.CCR-18-2572

    Low DRD5 expression is the main biomarker of response to ONC201 that has been identified. So yes, non H3.K27M-mutant gliomas could potentially respond to ONC201. But H3.27M mutant tumors have a higher chance of having low DRD5 expression, because "Further investigation revealed that H3.3 K27M appears to epigenetically suppress DRD5 expression, rendering tumors sensitive to ONC201."
    http://grantome.com/grant/NIH/R44-CA192427-04

    ReplyDelete
  3. Stephen, thank you so much! I’ll look through the report, probably there will be information about the quantity of the genes. It is Russian laboratory.

    How can I define DRD5 expression? Tumor sample, blood? Where it could be done?

    ReplyDelete
    Replies
    1. The DRD5 test would be an immunohistochemical test, looking at the protein expression of DRD5 in the tumor sample. I don't know where it could be done, this isn't a routine test for any type of cancer.

      Delete
    2. Most cancer labs would be technically set up to do it - they would just have to order the DRD5 antibody to carry out the testing. Which labs actually offer this commercially is another matter.

      Delete
    3. Thank you! We decidwd to try it without DRD5 test, because I read that scientists still do not fully understand what principle ONK201 works.

      Stephen, do you have any idea why onc201 needs 3-6 months to show at least some results? So says the doctor who can write a prescription for it.

      Сumulative action? But, if it is a blocker, then why is there no effect for example, in a month?

      Irina

      Delete
  4. Thank you!
    We decidwd to try it without DRD5 test, because I read that scientists still do not fully understand what principle ONK201 works.

    Stephen, do you have any idea why onc201 needs 3-6 months to show at least some results? So says the doctor who can write a prescription for it.

    Сumulative action? But, if it is a blocker, then why is there no effect for example, in a month?

    ReplyDelete
    Replies
    1. I'm not sure, maybe it has an immediate biological effect, but works slowly so it takes that long for the effect to actually become visible on an MRI. Another example of this is Optune, where some people whose tumors responded to it were wearing it for 2-4 months before any tumor shrinkage occurred.

      Delete
    2. We know that the biological target of ONC201 is dopamine receptors (DRD2) and DRD5 is a negative regulator of DRD2. So it does make sense that tumors with low expression of DRD5/ high expression of DRD2 would be the ones with a chance of responding to ONC201. But I can't say I know for sure that DRD2 is the only relevant target for the drug.

      Delete
  5. And one more question, please. What do you think abou Salinomycin IV treatment? https://www.cancertreatmentsresearch.com/salinomycin/

    ReplyDelete
    Replies
    1. Salinomycin hasn't been approved, so I'm not sure how one would access it.

      Delete
    2. In the article on Salinomycin you linked to it says the drug was patented by Verastem, but if you go to the Verastem website they don't mention it at all in the clinical trials section. It would appear the drug is in very early stages of development.

      Delete
    3. "VS-507" is mentioned in two papers cited on the Verastem website, but both these papers describe preclinical, not clinical research.

      Delete
    4. Stephen, we are familiar with the developer of salinomycin, it is a man from Russia who has been living with terminal cancer of the stomach for 4 years thanks to salinomycin (he had no chemo). He sold patent to USA. But we can buy it, 98% pure.
      We want to try it intravenously. What do you think about that? Does he cross the BBB?
      I saw some articles about glioblastoma and salynomicin invitro, but how it would be in vivo - big question.

      Delete
    5. I can't answer this question because human trials for brain tumors haven't been done. In mice bearing orthotopic gliomas (implanted into the brain), salinomycin prolonged median survival by only 2 days.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337630/ (see figure 5)

      Delete

    6. Dear Stephen!
      A few more questions please 🙏
      1) What do you think about this trial: https://clinicaltrials.gov/ct2/show/NCT02062827 ?
      2) What do you think about Regorafenib and glioblastoma (https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30675-2/fulltext)?
      3) What do you think about PVC RIPO (a lot information about it in Duke vebinar:https://virtualtrials.com/video2019.cfm?video=201901) ?
      4) And I can’t still understand about tetanus booster before some vacinations... when do the do it? The same day as vactination, previously for 5,20 days? How?

      Thank you!

      Delete
    7. Hi Irina,
      1) I like that trial in theory, but it's a phase 1 dose finding trial, which means we still don't know how well it's going to work in practise or what the optimal dose might be. Early phase trials are usually something of a gamble that way.

      2) I like the idea of regorafenib, but the monthly cost as of 2014 was listed as just under $10,000 USD. I'm not sure how insurance works where you are.

      3) I really like PVS-RIPO (modified poliovirus), it is one of my favorite trials. I've heard that Duke doesn't accept patients in their trials who don't have insurance in the USA. I'm not sure about the other trial locations.
      https://clinicaltrials.gov/ct2/show/NCT02986178

      4. According to this paper,
      https://www.ncbi.nlm.nih.gov/pubmed/25762141

      "Patients were randomized by side to have one inguinal vaccination site pre-treated with either 1 [million] unpulsed DCs or Td toxoid (1 flocculation unit (Lf)). Saline was administered on the contralateral side. Vaccination site pretreatment was done 6–24 h before DC vaccination"

      Also clinical trial descriptions give some of the details:
      https://clinicaltrials.gov/ct2/show/NCT03927222
      Biological: Tetanus-Diphtheria Toxoid (Td)
      Before the first DC vaccination, patients will receive 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Prior to pp65 DC vaccination #4,(3±1) weeks after leukapheresis 2 the vaccine site will receive a pre-conditioning intradermal injection of Td (1 flocculation unit (Lf), in 0.3 mL of saline for a total of 0.4 mL).

      https://clinicaltrials.gov/ct2/show/NCT03688178
      Group 2 patients will receive a single dose of Td toxoid administered to a single side of the groin and saline administered to the contralateral side the day prior to the 4th DC vaccine, which is always given bilaterally at the groin site.

      https://clinicaltrials.gov/ct2/show/NCT02465268
      Subjects in the experimental arms will receive Td skin prep before study drug doses #3, #6, and #9.


      So the answer to your question is that they administer the booster on the day before vaccine. They don't give it before every vaccination, but they may give it before every third vaccination as in the trial above.

      Delete
    8. This comment has been removed by the author.

      Delete

  6. Stephen, thank you so much! Your answers really help me.

    Could you please help me with the dosage and schedule of regorafenib with gbm?
    Should we make any blood or tumor analysis to know if it helps in our case?
    As I understand it works the same way as avastin, yes? (Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition)
    Could we take avastin and regorafenib together?

    The price for this drug in russia is about 2000$ for 84 pills (each 40 mg).

    ReplyDelete
    Replies
    1. Full text of the regorafenib paper is here:
      https://sci-hub.tw/https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30675-2/fulltext

      I can't recommend any specific tests to help predict regorafenib response. There were no biomarkers mentioned in the paper.

      "regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle"

      The only similarity of regorafenib and Avastin is that they both can have anti-angiogenic effects: Avastin blocks VEGF-A. Regorafenib inhibits VEGF receptors 1-3, but also inhibits PDGF receptors, RAF-1, and others, so it actually has a broader spectrum of activity than Avastin. This is useful, because some tumors might be driven by angiogenic pathways other than VEGF-A, and these wouldn't respond to Avastin but could respond to a different drug.

      In theory, yes you could probably combine the two drugs, although I've not seen studies on this so I wouldn't be able to comment on the safety or dosing.

      Delete
    2. Thank you so much! We will try!

      Delete