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Precision Medicine, Adaptive Clinical Trials, and Defeat GBM

President Barack Obama sent waves through the national news media when he announced during his 2015 State of the Union Address that he would be launching a “precision medicine” initiative.

“Obama Proposes U.S. Spending to Research Personalized Cures,” was the headline from Bloomberg. “What is President Obama’s ‘precision medicine’ plan, and how might it help you?” asked the Washington Post. “Obama urges more funds for ‘new era of medicine’” wrote Yahoo! “Obama to Request Research Funding for Treatments Tailored to Patients’ DNA,” exclaimed the New York Times.

But for those of us working daily in the field of biomedical research, this concept has been taking shape for years already. In fact, going back a number of years – and particularly with our 2013 launch of the Defeat GBM Research Collaborative – the National Brain Tumor Society began focusing on leveraging this “new era” of post-genomic sequencing to foster development of custom-tailored treatments for brain tumor patients.

“Precision medicine” – sometimes referred to as “individualized medicine,” “personalized medicine,” or “targeted therapy”– is, in basic terms, matching the right patients, to the right medicines, at the right time. This means gaining a deeper understanding of the specific molecular characteristics that are driving a patient’s tumor growth, and finding the right treatments to target those specific molecular abnormalities that are responsible for the disease.

This approach to biomedical research and medicine is particularly pertinent in the area of brain tumors, especially with the most common and deadliest form of brain cancer, glioblastoma multiforme (GBM).

GBM has four well-characterized subtypes, which can all respond differently to different treatments. Further more, GBM is one of the most heterogeneous tumors – meaning individual tumors might be made up of cancer cells, which have a wide-variety of molecular alterations and/or mutations. As such, it is not likely that one treatment will be able to serve as a silver bullet for all GBM patients. (This also helps explain why chemotherapy and radiation have been largely ineffective in treating GBM patients). What is more likely is that treatments, or combinations of treatments, will need to be administered to distinct subgroups (or subpopulations) of patients whose tumors harbor the specific molecular alteration(s) and/or mutation(s) that the medicines can specifically effect.

Defeat GBM Research Collaborative is a prototype for this type of approach. Defeat GBM is made up of four “cores” – or project teams. Three of these cores, listed here, are already successfully working simultaneously. The fourth core, focusing on adaptive clinical trial design is detailed further below:

  1. Target Discovery: Identify targets (the molecular alterations and mutations) within GBM cells that are driving the growth of these tumors.
  2. Drug Discovery: Find specific drugs, or combinations of drugs, that attack the targets that are being discovered.
  3. Biomarker (or Predictive Marker) Development: Identify specific biological processes that occur in GBM cells that can predict whether or not a particular drug, or combination of drugs, will be effective for a patient or group(s) of patients.

After researchers identify a promising target for treatment – say a mutation in a specific gene – they then find a drug(s) that is designed to attack the mutation, and finally identify the predictive markers that let scientists and doctors know what patients may benefit from the potential new drug. The next step, before a new treatment regiment is approved for use by patients, is to test it through the clinical trial process.

Traditionally, in GBM clinical trials any patients confirmed to have that tumor (and meet other inclusion/exclusion criteria) could enter the trial. But this type of trial approach alone likely will not be enough to get new, molecular/genomic-based treatments to patients, because it does not account for drugs that are being designed to precisely target specific alterations and/or mutations that not every GBM patient will have.

This is why the fourth core of Defeat GBM was created to house a “Smart” clinical trial; a trial that will match the correct subgroups of patients – as identified by molecular markers – to the right drug targeting the specific mutations and/or alterations that are driving their tumor. Building from previous planning and foundation building, the Defeat GBM Research Collaborative team is currently defining the development of what is known as an “adaptive clinical trial” with a number of partners both in the U.S., as well as internationally, including the originators of the I-SPY adaptive trials being done in breast cancer.

These types of trials allow for molecular subtyping of patients, and, thus, the matching of patients to the right drugs at the right time.

In order to realize the full potential of precision medicine, proper models for biomedical research and drug development need to be employed from basic (discovery) research all the way through the clinical trail process. This is why Defeat GBM is so powerful and unique. It was designed expressly to usher scientific findings through an end-to-end process of targeted, precision medicine development, as we seek new and better treatments for patients that move beyond a one-size-fits-all approach.

  • ganesh jagannathan

    Hi ,, It is very interesting to read this article. I appreciate the efforts put across to finda cure for GBM. My dad has been diagonsed with brain tumor and it is GBM.
    He was operated last month and now going through RT and Chemo using tablets.

    I want to see if i can avail any clinical trials for his treatment from India. If i can, i am ready to make him travel to US as well.

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