Last week, a colleague sent me a news story about a young girl whose glioma was in an advanced state and not responding to conventional treatments. Doctors from Dana-Farber/Boston Children’s Hospital’s pediatric neuro-oncology team tried a last-resort treatment for the young patient, and, miraculously, three years later, she has not only survived, but is thriving.
What’s more is that the treatment she received wasn’t even developed to treat pediatric brain tumors, but was a drug that, until that point, had only been used to treat adult skin cancer patients.
So why did a drug that was made for adult skin cancer patients work so well for a pediatric brain tumor patient? The answer lies in the power of molecular genetic profiling, the foundation for precision medicine. The young girl’s doctors had removed one of the seven tumors in her brain and done a molecular profile to test what specific alterations might be occurring that were causing her cancer. What they discovered was that her cancer had a mutation also found in some skin cancer patients—specifically adults with melanoma. And for those adult patients, there was actually a highly successful drug, dabrafenib.
My colleague’s email – which linked to this story – asked, “What are NBTS’ thoughts on this story?”
My answer: This is “precision medicine” at work.
Precision medicine is a major topic of interest to NBTS, as I explained in my January blog, which discussed NBTS’ priorities for 2016. Here’s what I said at the time about our research focus in 2016:
“…[We have] a single-minded emphasis on pushing the brain tumor research field farther into a precision medicine paradigm.”
In fact, we consider both our Defeat GBM Research Collaborative and Project Impact/Defeat Pediatric High-Grade Glioma initiatives prototypes for how to develop and apply a precision medicine based approach in the brain tumor field (Defeat GBM for adult brain tumors; Project Impact for pediatric brain tumors). The GBM AGILE trial that we are playing a role in will also aim to match patients with particular molecular “biomarkers” to treatments by identifying the molecular sub-groups of GBM patients who show the best responses to drugs that target specific molecular alterations.
Precision medicine – sometimes referred to as “individualized medicine,” “personalized medicine,” or “targeted therapy”– in basic terms, 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.
The means to this end can be accomplished through a couple different approaches.
One approach – and the one that the story above really relates to – is called “drug repurposing” or “drug repositioning.” This is where a patient’s doctor profiles that individual’s tumor, and then seeks to find an already FDA-approved drug from another disease area that might target a specific molecular alteration that patient’s tumor holds. A number of recent patient case examples – including the one above – present encouraging evidence of the effectiveness of using selected, targeted re-purposed drugs based on molecular profiling to treat individual brain tumor patients. In fact, there are now a number of clinical trials that are employing unique designs and structures to try this approach on a larger scale, including the National Cancer Institute’s MATCH trial and the American Society of Clinical Oncology’s TAPUR trial.
The other is a more “whole-cloth” approach to precision medicine development. In this approach researchers seek to find common molecular targets and pathways present in larger populations and subpopulations of patients based on broader-scale genomic sequencing data (as opposed to limiting results to an individual’s tumor) and identify and/or develop new chemical compounds or molecular agents – potential new medicines that haven’t been fully evaluated and approved yet – such as a drug or biologic. These could be re-purposed compounds, or novel (new) agents.
The common thread between these two approaches to precision medicine is, again, using molecular information to inform drug development and design clinical trials. Where the two approaches differ is in terms of scope and possibilities.
While a more straight-forward re-purposing approach can yield very big success stories – again like the one above – on an individual level, it has drawbacks when it comes to creating major change on a population level. Further, current repurposing efforts for brain tumors are limited to already approved drugs with a limited range of molecular targets, many of which weren’t designed for the specific challenges of treating a tumor in the brain, like crossing the blood brain barrier.
As NBTS is a population oriented organization, seeking better treatments and cures for all brain tumor patients, our research programs relate more with the second approach to precision medicine – a more broad-based effort that is prospective and includes but is not limited to the drugs and targets that were developed for other therapeutic indications.
Defeat GBM seeks, through a full-force research program, to uncover and develop new therapeutic targets and treatments that can ultimately be approved to successfully treat brain cancer patients who share molecular markers.
As we enter an era that anticipates more tailored therapies for brain tumor patients, NBTS research initiatives seek to address several challenges facing precision medicine. In particular, we need to understand the significance of whether targeting specific molecular alterations by therapies will be sufficient to have clinical benefit as not all molecular alterations are closely tied to driving tumor growth. In addition, given the complexity of brain tumors, it is likely that combinations of targeted therapies will be required to impact the course of the disease. Therapies themselves can produce changes in the molecular profile of tumors and cause drug resistance, so we need to be able to anticipate and block resistance pathways. As a field, NBTS believes we need to build a solid base of clinical evidence through prospective clinical trials to define the best therapies for specific types of molecular “signatures” found in brain tumors.
This way, in the future when patients are in the clinic and their doctor seeks to match their tumor’s molecular profile to available drugs, they will have more truly precise options designed specifically for brain tumors.
Until then NBTS still encourages all brain tumor patients to ask their medical team about all potential treatment options, including standard-of-care, clinical trials, as well as understand individualized treatment based on molecular profiling.
While much work remains, I remain encouraged daily by what is currently unfolding in the brain tumor research field. These developments include an anticipated update to the World Health Organization Classification of Tumours of the Central Nervous System. This will be the culmination of years of research that have allowed us to better understand the biological/genetic/molecular make-up of brain tumors, and will move the field to a classification system that incorporates molecular information into diagnoses, which should lead to improvements in diagnostic consistency, prognoses, and predicting the success of therapies.
This will be a really big step in further creating a foundation for precision medicine in brain tumor research and treatment. As a researcher recently told us, “The evolution from the annals of history of histopathology (classifying/diagnosing a tumor based on what it looks like under a microscope) to where we are now (incorporating molecular information), really coincides with the dawn of precision medicine.”
This doesn’t mean that precision medicine will now be fully realized in neuro-oncology (again we still need more and better, brain tumor-specific targeted treatments), but having more accurate and precise diagnoses and classifications is the foundation on which precision drug development can advance. That’s where the research programs of NBTS and others will make the difference.
Bottom line: the field is moving forward toward precision medicine in a positive way.
With Sincere Gratitude,
David F. Arons, JD
Chief Executive Officer
National Brain Tumor Society