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Defeat GBM Research Collaborative Produces Important Discovery

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As we wrote on this blog back in May, the issue of “acquired resistance” is one of the biggest challenges in successfully treating brain tumors. Acquired resistance refers to tumor cells’ ability to learn to dodge the effects of treatment. Once a tumor develops resistance, current drugs stop working and the tumor can resume growing.

The issue is of such importance to developing new, more effective drugs for brain tumor patients, that one of the four teams in our Defeat GBM Research Collaborative, is dedicated to identifying what causes acquired resistance in glioblastoma multiforme (GBM) cells. This team – the Discovery team – is led by Drs. Webster Cavenee and Frank Furnari at Ludwig Cancer Research, San Diego.

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Dr. Webster Cavenee, PhD

Drs. Cavenee and Furnari now believe they may have identified a mechanism by which GBM cells become resistant to certain, initially promising treatments.

A gene called EGFR is the most commonly mutated oncogene (a gene that has the ability to cause cancer) in GBM. But therapies that have been developed to target and block EGFR’s ability to drive tumor growth (so-called EGFR inhibitors) have not produced long-lasting benefits for patients, to date.

How GBM cells are able to develop the ability to dodge EGFR inhibitors has not been well understood. This new discovery, enabled through Defeat GBM funding, gives researchers a clue to how resistance is developed.

The Discovery team studied resistance in new pre-clinical models of GBM tumors that no longer respond to treatment with EGFR inhibitors. They found that in the drug resistant tumors, a molecule called uPA appeared frequently at abnormally high levels. The researchers were able to determine that high-levels of uPA in the tumor cells caused a decrease in levels of an important protein called Bim. (Bim is key to a process that causes cells to die a healthy death, as opposed to replicate out-of-control, as is the case in cancer/tumors).

The conclusion: when you treat GBM tumors with EGFR inhibitors, the tumor subsequently increases its level of uPA, which triggers a process that results in the decrease of Bim. Without enough Bim the tumor cells are able resume growing.

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Dr. Frank Furnari, PhD

However, the Discovery team also believes that it might be possible to therapeutically restore the function of Bim, and thus block the tumors growth yet again. “By using drugs that mimic the activity of Bim, or block the pathway initiated by uPA activity, we feel there is an opportunity to overcome EGFR inhibitor resistance,” said Dr. Furnari.

Excitingly, this discovery immediately activates work in the Defeat GBM’s Drug Development core (taking place at MD Anderson) to find combinations of EGFR inhibitors and other therapies that will successfully treat GBM patients with these mutations and alterations in their tumor. This accelerated transfer of findings from Discovery to Drug Development is a testament to structure and power of the Defeat GBM Research Collaborative.

To learn more about the program, please click here. To help support the program, click here.

  • Debbie Starling

    My husband died 4 years ago from GBM, at the time he did the temodar/radiation/clinical trial of some sort and then finally avastin. He was diagnosed in January of ’08 and was only expected to live 3-12 mos. at the time. He lived until August of ’10! the Dr.s were amazed but I feel he did not have the protein? to block the initial temodar and so that was successful for almost a year before the little buggers figured out a way around that drug. I wish this information was available back then he might still be with us. But so happy there is strides going forward its a horrible disease.

    • Sheira Cliff

      So sorry to hear of your husbands death . Xxxxx
      Will this be available in the UK and hiw can we access it.
      Thanks
      Sheira macintyre

      • TomHalkinNBTS

        Hi Sheira – Thank you for reading. This work is still in the preclinical phase, meaning there is more work to be done before this becomes a treatment options patients can receive in the clinic. We will provide updates on this and more discoveries that come from our Defeat GBM Research Collaborative as they happen. Best Wishes – Tom.

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