“We have the team approach to be able to address these diseases”
- Professor Webster K. Cavenee, Ph.D. Director, Ludwig Institute for Cancer Research, San Diego
There’s no doubt that brain cancer research is a team game and the players are now competing together in an international league, all focused on the same goal: finding a cure. But to formulate a game plan it’s important to have all the information to hand.
Assessing the field of play
A literature review looks at all of the peer-reviewed, scientific papers published in a specific research area for a certain time period. Our literature review looked at brain cancer research papers published from 2010 to 2014. Wading through paper after paper of scientific jargon and reviews on what’s new in brain cancer research allows the reviewer to provide a condensed overview of the field of play, enabling analysis of where all this research is taking us. Although the prognosis for brain cancer has hardly changed for many years, we are inching closer to a tipping point.
So what are the game changers in brain cancer research? According to the literature review and current news, precision medicine and immunotherapy are shaping up to be the star players.
A more thorough overview of the 2014 Literature Review can be accessed here.
Causes of brain cancer
It’s been called “the monster”, by Professor Inder Verma, an eminent cancer researcher from the Salk Institute. Many people have other choice phrases to describe the disease. Whatever you call it, one thing’s for sure: brain cancer is a tricky beast to tackle.
We still know very little about what causes brain cancer. Ionising radiation and certain genetic syndromes are the only established risk factors.
As world–renowned neurosurgeon and neuroscientist Dr Keith Black from Cedars-Sinai Medical Centre said in a recent interview with Cure Brain Cancer:
"We believe most brain cancers occur spontaneously. We know like for all cancers, there are some genetic influences. But we haven’t identified anything as obvious as, say, cigarette smoking for lung cancer. My suspicion is that most brain tumours are spontaneous mutations.”
- Dr Keith L. Black
To date there is no conclusive evidence that brain cancer is caused by any of the following: electromagnetic fields, head injury, foods containing nitrates, aspartame, occupational risk factors, pesticides, or season of birth.
As so little is known about what causes brain cancer, the research literature tends to focus on new treatment approaches rather than prevention.
Here in Australia, the current standard of care for patients follows international best practice guidelines. Glioblastoma (GBM) is the most common and deadly form of malignant brain tumour, and so much of the treatment information that will be discussed below focuses on GBM.
Existing treatment for newly diagnosed GBM includes surgery, radiotherapy and chemotherapy. There is currently only one type of drug for the treatment of GBM, called temozolomide. Although these therapies remain incredibly important to the survival time of GBM patients, unfortunately they rarely extend life for longer than 14 months. Current research is focused on a way to make standard treatment more effective and finding new therapeutics that will lead to a cure for brain cancer.
Surgery remains one of the mainstays of brain tumour treatment and thanks to advances in research there are now new surgical techniques and procedures that are expected to make it far more precise.
Intraoperative magnetic resonance (iMRI), allows surgeons to clearly see brain tumours while operating.
‘Tumour paints’ are drugs that make cancer cells glow so that surgeons can more accurately differentiate the tumour tissue from healthy brain tissue whilst operating. There are a couple of tumour paints being trialed, including 5-ALA fluorescent markers , which ‘tag’ the tumour cells, and a radiolabelled drug that was originally derived from scorpion venom (131-I- labelled synthetic cholortoxin). These techniques are being explored to allow surgeons to remove as much of the cancer as possible without damaging surrounding brain tissue.
Minimally-invasive surgery is another breakthrough in brain surgery performed through the smallest incision possible. Minimally-invasive surgery is aimed at increasing efficacy of surgery whilst reducing trauma to the brain, recovery time and post-operative pain.
Until recently, whole-brain radiation therapy was the treatment of choice for brain cancer. Now, stereotactic radiosurgery (such as Gamma Knife and Cyberknife technology) is being used in some patients and is a way of targeting radiotherapy very precisely at the tumour. It gives a high dose of radiation to the tumour and a lower dose to the surrounding healthy brain tissue, reducing side effects. It’s a non-invasive option suitable for certain types of tumour and can be performed as an outpatient procedure.
Like surgery, radiotherapy is moving towards image-guidance. Used in combination with radiotherapy imaging, radiographers can see the tumour and brain as they are treating them. It’s been recommended that future prospective trials for brain cancer include image-guided radiotherapy to assess the impact on the patient quality of life.
Read more about radiotherapy for brain cancer here.
As we have seen, existing treatments like surgery and radiotherapy remain important and are key players in brain cancer treatment. But there is a limit to what they can achieve. So what progress is being made in other leading areas of treatment?
The Game Changers
One characteristic of all cancer cells is the presence of multiple changes at the molecular or DNA level. These include gene mutations and epigenetic changes (changes to gene expression that are not due to changes to genetic sequences) which kick-start or stop mechanisms that control tumour growth and proliferation.
From a molecular standpoint, another finding to come out of the literature is that brain cancer is highly heterogeneous, meaning each tumour has many different genes, molecules and cell types in it. For this reason, combinations of treatments are needed destroy the different cell types.
“Even within the same patient they’ll have different genetic alterations driving the same tumour… so we’re going to need very broad therapies to make a difference”
– A/Prof Terry Johns, Director, Brain Cancer Discovery Collaborative
Thanks to our evolving understanding of the molecular biology of tumours, their microenvironment and the role of the immune system in the development and spread of cancer, a number of new therapies are undergoing clinical trials at the moment. The majority of these are focused on:
- Identifying ways to overcome temozolomide resistance (as most tumours eventually develop resistance to temozolomide)
- The development of molecular targeted and anti-angiogenic agents (agents that prevent the formation of new blood vessels)
- Drug combinations
As cancer research has evolved, the focus has shifted to understanding how cancer functions on a molecular level – and it’s paying off.
Projects like The Cancer Genome Atlas to sequence tumours have evolved our understanding of cancers dramatically. In some cases, like medulloblastoma for instance, what was previously thought of as one disease is now known to have at least four molecular sub-types, which are all different and require different treatments.
Greater understanding of the genetic mutations and molecules involved in the growth and proliferation of different brain cancers has led to the emergence of ‘precision medicine’. By understanding a specific tumour’s mutations, researchers can develop therapies to target them, increasing the efficacy of the treatment whilst reducing the side effects. These targeted therapies are the superstar strikers.
The ever-expanding literature on genes and molecules involved in brain cancer is driving precision medicine. As a result, treatment is moving away from the one-size-fits-all treatments of the past to ‘designer drugs' better suited to an individual patient. Precision medicine is one of the four pillars of Cure Brain Cancer’s research strategy and was a hot topic of conversation at the recent Cure Brain Cancer International Scientific Meeting.
The Era of Immunotherapy
The discovery that gliomas are less likely to develop in people with diseases such as asthma, eczema, and hay fever highlights the importance of understanding the role the immune system plays in brain cancer. Immunotherapy relies on stimulation of the patient’s immune system to increase the immune response to target tumour cells. A variety of vaccination approaches are in various stages of clinical development both here in Australia, and globally, based on encouraging, albeit preliminary, evidence of therapeutic benefit from clinical trials. These are the star defenders on the team.
As pointed out by the CEO and Research Director of the Translational Research Institute, Professor Ian Frazer AC (who developed the cervical cancer vaccine Gardasil), neuro-oncology has finally entered “the era of tumour immunotherapy”. This is an important focus of Cure Brain Cancer's research strategy.
“To be able to vaccinate against a brain tumour is beyond our wildest dreams, but it’s happening now”
– Dr Kerrie McDonald, Head CBC Neuro-oncology Group, Lowy Cancer Research Centre.
Drug repurposing involves using drugs not traditionally used to treat brain tumours which have been used successfully to treat other diseases. It typically takes as long as 20 years to get a new drug to market, because of the rigorous testing procedures it has to go through. Drug repurposing allows researchers to get useful therapies to patients faster, because the drugs have already been shown to be safe and effective in humans in other diseases, bypassing years of the drug development pipeline. Drug repurposing is something the Brain Cancer Discovery Collaborative (BCDC) is working on right now in Australia.
The International Initiative for Accelerated Improvement of Glioblastoma Care has proposed a new nine-drug combination to be tested in patients who develop brain tumours again after their initial treatment. Cure Brain Cancer’s research strategy supports drug repurposing to speed up the time it takes to get new therapies to patients. It is the way of the future for many cancer treatments.
Another emerging area is the use of nanotechnology to overcome the physical difficulties of delivering drugs to targets in the brain.
Nanoparticles have been studied as a method of getting treatments across the blood–brain barrier and through the tightly-packed brain cells. Such particles may provide a new method for targeted drug delivery.
A recent example is the use of microbubbles and drug-loaded nanoparticles coated in polyethylene glycol by the University of Virginia and Johns Hopkins University. When excited with ultrasound, the microbubbles open up tiny holes in the blood vessels around the tumour allowing the loaded nanoparticles to move freely through the brain and attack the tumour.
Targeting cancer stem cells has emerged as another treatment option. Stem cells are ‘blank’ cells that can be written into any type of cell. They are fast growing and can drive tumour progression because of their self-renewal capacity and limitless proliferative potential. Recent findings show that cancer stem cells may also contribute to the resistance of malignant gliomas to chemotherapy and radiotherapy.
Recent research has discovered that three existing drugs - sorafenib, disulforam and metformin - may have potential with a direct effect on cancer stem cells viability in a number of tumours including glioblastoma.
Distinguished Professor Webster Cavenee has said that brain cancer research is at a “unique inflection point”.
For newly diagnosed patients it may not feel like much progress has been made, as standard treatment remains a combination of surgery, radiotherapy and chemotherapy, as it has for years. It might seem like there is a lot of talk about these ‘new era’ treatments, but you aren’t seeing any action. It takes time and there are many pieces of the puzzle to put together, but we are on the brink.
The game changers are lining up in the tunnel about to step onto the pitch, with a number of precision medicines and immunotherapies currently being tested clinically. Once they come into play we will enter a new era of brain cancer treatment – and start scoring more goals.