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Glioblastoma Is Bad News, Period

Everyone keeping up with the news will have heard about Sen. McCain’s diagnosis of glioblastoma multiforme (GBM). This is not good news at all; GBM is a very aggressive tumor type for which treatment options are poor. The contrast to ex-President Jimmy Carter’s brain cancer experience is stark, and many people outside the biomedical field must be wondering why the two are so different.

Carter’s diagnosis was metastatic melanoma, which until very recently was just about as bad an answer to get as GBM. Surgery and radiation have been the standard combination for melanoma, but the metastatic form of the disease is much harder to deal with, since it has, of course, spread to other organs at that point. But immunotherapy has been added to that in recent years, and that’s what tipped the balance in President Carter’s case. Many metastatic melanomas are particularly dependent on PD-1 as a mechanism to keep T cells from recognizing and attacking them, and the antibodies targeting that protein have shown themselves to be quite effective. Unfortunately, GBM is another thing entirely, and illustrates the problem that cancer is really a collection of thousands of different diseases.

Glioblastomas are characterized by extreme genomic instability, even by the standards of cancer cells, meaning that what appears to be a single tumor is almost certainly a large collection of different cell types using different mechanisms to grow and survive. That explains why no single therapy has had much success in the field. The standard treatment is temolozomide, which is really a brain-penetrating prodrug that produces the same species as another chemotherapy agent, dacarbazine. That’s a DNA alkylating agent, so we’re now back into the classic (and brutal) form of chemotherapy, where you’re damaging dividing cells in general, but damaging the rapidly dividing ones even more (dacarbazine is, in fact, used to treat metastatic melanoma as well). It’s also a prodrug itself, and organic chemists will be alarmed to find out that it breaks down to diazomethane, which is what does the actual methylation of guanine bases in DNA. Cancer therapy with a systemically dosed diazomethane precursor sounds pretty primitive, and it is. But that’s the best we have for GBM.

Many attempts have been made at improving this situation, and one of the most notable was the idea of placing slowly dissolving wafers containing the chemotherapy agent carmustine at the site of the tumor directly after surgical resection. This makes a lot of sense, as the recurrence of GBM after surgery makes it clear that it’s impossible to do a clean-margin removal of the cancer tissue. Carmustine is a really rough compound, a combination of a nitrogen mustard and a nitrosourea (which is a diazomethane precursor, as those who have made the reagent in the lab well know). Unfortunately, the wafer (brand name Gliadel) has not seemed to demonstrate any advantage in survival compared to regular temozolomide treatment, at least not in randomized trials (cohort studies have looked better). So it’s not clear if there’s a real advantage in using it.

As you would figure, all sorts of approaches have been tried against GBM, with a conspicuous lack of success. One that remains to be tested is the use of a GSK3 kinase inhibitor along with radiation, which has shown promise in model studies. Let’s hope that this translates into efficacy in humans, because something efficacious is badly needed in this field. It’s a really tough one.

43 comments on “Glioblastoma Is Bad News, Period”

  1. Immunobiologist says:

    I think we’ll need something exotic like oncolytic viruses to take out GBM, one of the worst villains of cancer.

    1. Ian Malone says:

      A guy I knew as an undergrad will soon be working on just that! http://crukcambridgecentre.org.uk/users/hb252

    2. Baltic says:

      That may be a promising approach, eventually. Sadly, like many other potential “cures for cancer”, this field is not without its ‘black sheep’, and there are companies offering oncovirus-based treatment options that sound promising, but turn out to be lacking the required evidence for supporting their efficacy. As an example, there is a product involving oncolytic virus called RigVir – and the company providing it have been fined for unfair commercial practice (and there are many other things in the story that seem somewhat shady) – more on the topic here: http://skepticisms.lv/enciklopedija/rigvir-when-science-takes-a-back-seat/

    3. Konrad says:

      The problem with glioblastoma is that is is extremely polymorphic. This tumor occurs when severe chain of mutations have had occurred. Even within single tumor one can find areas with very different genetic makeup. There is no one standard glioblastoma and so there is a giant problem with universal treatment. Also pattern of its growth makes is virtually impossible to be wholly removed during surgery.

    4. Mes says:

      You mean Zika I guess

  2. dearieme says:

    I gather that when doctors themselves are patients they can be quite selective about which cancer treatments they accept. Is this one of those cancers where they might well decline treatment?

    1. Immuno-oncologist says:

      No, Temodar is actually fairly well tolerated. Derek is right the the treatment is not super efficacious and somewhat primitive, but it’s not one of the super toxic chemos. Also, there are a small fraction of GBM patients who get a moderately durable response to temodar + radiation.

      1. dearieme says:

        Thanks.

    2. Immuno-oncologist says:

      Here is the original NEJM study showing efficacy of temodar, especially with MGMT gene methylation: http://www.nejm.org/doi/pdf/10.1056/NEJMoa043331

  3. johnnyboy says:

    multiforme* (no a)

  4. lynn says:

    Just read about this yesterday. Possibly hopeful CAR-T therapy for GMB?: O’Rourke, D. M., M. P. Nasrallah, et al. (2017). “A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma.” Science Translational Medicine 9(399).

    1. paperclip says:

      CAR T cells for GBM may indeed be promising, with a long way to go. My quick take from that paper is that 9 of the 10 patients did not have any response. And even for ones that do, antigen escape is going to be a hurdle.

    2. Mark Thorson says:

      Then there’s always the electric cap.

      https://www.statnews.com/2017/07/20/mccain-cancer-electric-cap/

    3. JB says:

      How the hell does it get into the brain?

  5. ACA+ says:

    Fortunately, Senator McCain is assured the highest standard of medical care, given his status and his gold-plated government-funded health care coverage. It’s ironic, given that millions more Americans are at risk of losing basic health care coverage, due to the misguided (and heartless) repeal-and-replace republican agenda to eliminate the ACA. Wouldn’t it be refreshing if McCain’s circumstances prompted bipartisan cooperation to actually resolve a failed health care system – unfortunately, there’s a different form of cancer in play in Washington D.C. and the United States these days.

    Best wishes to any one dealing with a personal health crisis like this, especially those on the margins.

    1. Me says:

      It would only be ironic if the new medical insurance bill was McCain’s pet, as opposed to something he has publicly complained about.

      The Affordable Care Act is, to be blunt, a tremendous trainwreck that consists primarily of forcing people to buy products from the same companies that ruined american healthcare in the first place, with many of the measures intended to protect the taxpayer-hostages from systemic abuse proving inadequate or simply unenforced. It desperately needs to be torn down and replaced by something else.
      BUT, and this is the important part, the American Care Act/Better Care Act/whatever they’re calling it today is an EVEN WORSE trainwreck and is by no means the needed replacement.

      Non-politically, I wish McCain the best of luck. He needs it right now.

    2. LiqC says:

      Sam Gambhir, a renowned Stanford professor, summoned every resource imaginable when his son was diagnosed with GBM. They put up a good fight, but it was still over in under two years. It’s the absolute anti-jackpot to come across…

      Link to the story is under my username

  6. Anon says:

    Good write up. Late Sen. Ted Kennedy also succumbed because of GBM. Just curious even if immune or CAR-T therapy is possible how east it is for these antibodies to make through BBB or am I missing something? I have known situation where they inject the medication directly into tumors, and I wonder if it can work?

    1. Mark Thorson says:

      I suppose you might inject them into the CSF where spinal taps are done.

    2. johnnyboy says:

      Malignant tumours have messy vascularization, so the BBB is assumed to be fairly leaky within brain tumours like GBM; theoretically large molecules would have some access to brain tumour cells. However GBM is not currently a very common indication for immuno-oncology drug trials, in part because it’s probably the highest bar to set for any drug. BMS tried with Opdivo and if failed. IO is still in its infancy and a relatively blunt instrument – more must be learned about the immune processes involved in the response to different tumour types before you could tailor an effective therapy for GBM.

  7. pjk says:

    The story of Temozolomide is quite interesting in case anyone is interested
    http://www.rsc.org/images/TEMOZOLOMIDE_ChemistryWorldJul09_tcm18-155909.pdf
    Cancer Treatment Reviews 1997, 23, 35-61

    The synthesis (on paper) also scares the bejesus out of me a little.

  8. luysii says:

    If you were choosing a brain tumor to have, glioblastoma multiforme would be your absolute last choice.

    For the record, although glioblastoma multiforme is definitely a tumor of the brain, it is equally definitely NOT a tumor of neurons, but of glial cells. Neuronal tumors of the brain are exceedingly rare, and I never saw one in decades of practice.

    It is worth considering why. Neurons essentially never divide (recent evidence to the contrary shows that such division is quite rare and limited to a small number of neuronal types) which is why neuronal loss is so devastating. Perhaps the lack of copying errors during mitosis is in some way protective against cancer.

  9. GermanMedChem says:

    If you want to better understand what GBM is all about: Wolfgang Herrndorf – Arbeit und Struktur. I don’t know if it has been translated into English but it is definitely worth reading.

  10. Dell says:

    Great reminder that life is short and so blowing your 20s doing western blots for an entitled professor that treats you poorly is a very bad idea

    1. newpostdoc says:

      you, kind sir, make a very good point!

  11. Donald Trumped says:

    Reminder that there is NO CURE FOR CANCER, this industry is nothing but people trying to make drugs/therapies that will ultimately breed a more and more aggressive cancer by each generation.

    1. Chris Phoenix says:

      On most blogs I’d be slower to suggest censorship. But on a science/medicine blog, surely comments as wrong as this one are worth deleting?

      In case it isn’t deleted: Cancer isn’t transmissible between people, so “breeding” cancer is a null concept. Also, some cancers are indeed curable. Early-phase testicular cancer has an extremely high cure rate.

      1. Mister B. says:

        What about genetic markers ? Some of them have revealed to be really useful, in breast cancer testing for example !
        Sure, cancer isn’t transmissible as itself, but because of genetic transfer, one can have higher probability to get cancer.

        (That brings to me that, due to family history, I am tested for male breast cancer, something I ignored it could happen 😉 )

      2. G says:

        It’s certainly possible to increase the propensity of developing cancer through transmissible means (HPV, https://www.cancer.org/cancer/cancer-causes/infectious-agents/infections-that-can-lead-to-cancer/viruses.html).

        Agreed that contracting HPV virus does not in itself guarantee cancer, but it’s enough of a risk to warrant vaccine. And certainly HIV became known from AIDS / Kaposi sarcoma (tail wagging the dog)?

        Certainly the post was aiming low to “engage”; working for a company that will reduce liver cancer occurrence (curing HCV will help in that regard) is a mark against their emotionally driven thesis.

      3. David Cockburn says:

        No, it’s important to be remi9nded once in a while just how wrong headed some people are.

    2. Alchemist says:

      Given the alias used, I assume this is satirical. Right? Please?

    3. creator says:

      There is no cure for glioblastoma multiforme*

      Fixed that up for you.

    4. Vader says:

      Nec cibos troglodytam

    5. Thomas says:

      I agree with ure statement it’s all about the ppl who make the drugs for these disease

  12. gippgig says:

    Temozolomide looks like one of those compounds you wouldn’t want to work with. Is it as explosive as it looks?
    How much study has been done on combining temozolomide with an alkylation scavenger that doesn’t cross the blood-brain barrier?

  13. steve says:

    Just a small correction. BBB is not a barrier to treatment; there are well-established ways of cannulating and perfusing the brain with whatever drug you want. The problem with glioblastoma is its stem-cell like nature. This confers resistance to most treatments. Oncolytic viruses and immunotherapy both do seem the most promising but also are early-stage. This is a tough one and rivals pancreatic as the least treatable.

    1. Pennpenn says:

      It may not be an absolute barrier but I’m guessing that people would rather find ways of getting it in without drilling holes in the skull (an oversimplification, but I hope you get my meaning).

      1. steve says:

        They’ve likely already had surgery to remove bulk tumor so leaving a catheter in for perfusion is no big deal.

  14. Gordonjcp says:

    https://en.wikipedia.org/wiki/Carmustine

    From a non-chemist point of view (okay, I got a B for Higher Chemistry in high school but that was 25 years ago) that doesn’t even look like a drug. That looks like you’re just going to beat the cancer to death with a tyre iron.

  15. JM says:

    This Nov 2016 article discusses Phase II trials of pembrolizumab (PD-1, KEYNOTE-028) and durvalumab (PD-L1, MEDI4736) in glioblastoma. A small subset of patients showed improved PFS and in the latter case the response in that subset was very durable (12-15 months at time of publication).

    http://www.onclive.com/conference-coverage/sno-2016/phase-ii-trials-with-pembrolizumab-and-durvalumab-show-promise-in-glioblastoma

  16. Ana Aitawa says:

    We have published a research study on global Glioblastoma multiforme drugs market segmented by drugs used (Bevacizumab, Temozolomide, Carmustine). The analysis estimates the global market to reach nearly US$ 850 Million by 2021, growing at 13.4%CAGR over 2017-2021 forecast period. For more details, visit https://www.ihealthcareanalyst.com/report/glioblastoma-multiforme-drugs-market/

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