Glioblastoma Brain Cancer

Breakthroughs and Developments

Glioblastoma multiforme (GBM) is the most common brain tumor and one of the deadliest cancers in the world. It killed Ted Kennedy, it killed Beau Biden, and it killed my dad. According to the National Brain Tumor Society 17,000 people died of GBM in the United States in 2016.

W.K. Alfred Yung, M.D. has been at the University of Texas MD Anderson Cancer Center in Houston for the past 35 years. After building the center’s first neuro-oncology department he currently serves as a Professor of Neuro-Oncology and Cancer Biology and is also a member of MD Anderson’s Glioblastoma Moon Shot Initiative. In 1981, the year I was born, Dr. Yung began his practice at MD Anderson. At that time the average survival for people diagnosed with GBM was 9 month. Today the average survival is about 18 month. My father lived 24 months. This is progress, but it is frustratedly slow progress and far short of anything reasonably resembling remission or a cure.

Today, almost 35 years later, Dr. Yung is hopeful. Advances in genomic sequencing along with new technologies for detecting early-stage cancers and the identity of tumor-associated mutations, are allowing doctors to monitor disease progression and better understand the biology of individual brain tumors. This type of precision or targeted medicine could allow us to accelerate progress in the treatment of cancer by better targeting the tumors on a case by case basis. However, before we can turn that potential into an available treatment more research funding is needed and open source collaboration of research data is essential. And we are talking “Big Data”.

Big Data

Big data holds the key to unlocking breakthrough treatment for cancer. Scientists and physicians now understand that cancer is not a single disease. Cancer is many diseases which all have one thing in common; the rapid, uncontrolled growth of cells that invades tissue and is ultimately fatal if untreated. One group trying to do something about that is The Dragon Master Foundation. They recognized that while we have made some progress, and have made some patients’ lives better, 18 to 24 months is not good enough.

Advances in Research

The greatest challenge to treating GBM is that it is located in the brain. This adds a significant clinical hurdle because of the blood brain barrier (BBB). The BBB is a highly selective, semi-permeable membrane that separates the blood in our body from the extracellular fluid in the central nervous system (CNS). Being in the brain also means that side effects from treatment are more serious. Some of the biggest advancements in the treatment of GBM have been surgical and radiological. Cancer treatments typically results in massive inflammation which can be fatal in the brain. This makes the treatment of cancers in the brain even more challenging given the relative resiliency of the rest of the body to more aggressive treatments including total resections.

Over the past 30 years, surgical techniques and technologies have advanced in major ways. The ability to target and resect tumor without damaging healthy brain tissue has meant significant improvements in the quality of life for patients with brain tumors. More precise radiation machines driven by more precise imaging of cancer tumor cells has protected patients from even more serious side effects than they already suffer.

Dr. Yung expects that those surgical and radiological techniques will continue to develop along with thermal and ultrasound therapies. The integration of all these tools will continue to guide the primary care treatment of GBM in most hospitals. Personally this supports my generally belief that when it comes to cancer, if you can cut it out than get it out. Surgery beats out most new treatments for cancer and consistently stands as the gold standard for improving overall survival. Notwithstanding the quality of life side effects, surgery and advances in technology have been significant in keeping people diagnosed with GBM alive longer than they would be without surgery.

Unfortunately surgery is not going to cure this cancer. GBM is like a many tentacled octopus that invades and takes over the brain through the glial cells, which are the cells that surround the neurons providing support and insulating the nerves. This means the only way to surgically remove GBM, with clean margins, would be to remove the brain. And that is really not an option.

Immunotherapeutics

The most promising research today involves a better understanding of the metabolic differences between cancer cells and healthy cells. Targeting these differences is driving the development of targeted immunotherapies. These new therapies not only target the cancer tumor cells specifically, without damaging healthy cells, but stimulate the patients own immune system to begin attacking the tumor cells.

In the past, treatments have focused on targeting the feature that made all cancers the same; their tendency to rapidly divide, invade healthy tissue, and hijack our body’s metabolism to fuel their growth. This next generation of treatments rely on the unique qualities that make each cancer unique.

Cancer in organs of the body, other than the brain, have seen more progress when it comes to targeted immunotherapies. Solid tumors like lung cancer, bladder cancer, and melanoma all have promising immunotherapies that inhibit or activate a specific immune response.

When you start looking at difference, you find many overlapping areas where the growth and invasive qualities of cancer tumor cells are driven. There are multiple metabolic pathways which regulate immune response and modify the tumors microenvironment. Unfortunately we know little about how the immune system operates in the brain. Scientists only recently discovered a series of lymphatic vessels in the body that link the brain to the immune system, a connection researchers had previously thought didn’t exist.

T-cell therapies are particularly unsuitable for GBM since they work by making the immune system more active, inviting more inflammatory immune cells to the tumor, and causing all kinds of issues in the brain. The brain would swell up and the patient would die quickly. This may not be the case in other parts of the body.

Another promising area is Viral Therapy. Viral therapies are a kind of gene therapy that aims to use viruses to target and change the DNA of cancer tumor cells allowing them to be targeted and destroyed by our immune system. This method has similar problems to targeted T-Cell therapies but are more likely to be manageable. One promising viral therapy for GBM involves using a modified poliovirus. Early trials have been promising enough that the FDA has fast-tracked its development.

Cannabinoid Therapies

Another exciting development that we’ve been watching closely is the integration of cannabinoids into standard of care treatments. Cannabinoids have long held interest for researchers who have shown them to have both direct and indirect activity targeting cancer cells. The later has recently been subjected to the first placebo controlled study of combined tetrahydrocannabinol (THC) and cannabidiol (CBD), with temozolomide. Temozolomide is a chemotherapy drug that’s been used by itself to slow the progression of GBM and modestly improve overall survival.

These latest results come from an exploratory Phase 2 placebo-controlled clinical study of THC and CBD in 21 patients with recurrent GBM. The study showed that patients with documented recurrent GBM treated with THC:CBD had an 83 percent one year survival rate compared with 53 percent for patients in the placebo cohort. Median survival for the THC:CBD group was greater than 550 days compared with 369 days in the placebo group. That’s a 33% improvement in overall survival. The combined THC and CBD was generally well tolerated, only two patients in each group were forced to withdraw from the study due to side effects

“The findings from this well-designed controlled study suggest that the addition of a combination of THC and CBD to patients on dose-intensive temozolomide produced relevant improvements in survival compared with placebo and this is a good signal of potential efficacy,”

— Professor Susan Short, PhD

These promising results appear to be distinct from existing oncology medications and may offer a unique and possibly synergistic option for future glioma treatment.

Future goals

The greatest challenge in the future may be choosing the right combination of therapies that will be most effective for an individual cancer. This requires evaluating a multitude of factors that may not always yield clear and obvious results. Treatment is likely to remain both an art and a science, as doctors feel their way through the evidence and determine the best way to treat their patients. We still need to better understand the biology of this deadly brain cancer before we will be able develop a real cure. That is going to require a great deal more fundamental understanding of how cancer occurs in the body and also how it grows and spreads.

We also need better tools for describing the differences between individual cancers and how those changes are driven by the genes and the environment. That will allow us to develop better therapies that can target the multiple ways in which cancers grow and spread throughout the body. This will only happen if researchers are able to innovate and collaborate across institutions, sharing their data and, of course, their outcomes.

Beyond the horizon, new treatments will likely rely heavily on our improved understanding of the genetic makeup of GBM. While we know more than ever about the genetics of this disease, we have not yet been able to translate that information into more effective therapies. There are many promising new targets but no new drug therapies have been developed. In the meantime, we are getting better at combining therapies to maximize their effectiveness.

GBM treatment today involves surgery, radiation, and chemotherapy along with co-administered drugs to manage seizures and inflammation. Anti-inflammatory and anti-angiogenic drugs are frequently used to reduce symptoms and improve the effectiveness of the treatment. Future treatments are likely to evolve from this effort to incorporate primary treatments along with other complementary or alternative therapies which are popular among patients facing an incurable form of cancer. Some cancers are biologically simple such as leukemia, which is caused by a single pathway. This simplicity is why it has become one of the most treatable forms of cancer. GBM is a much more complex cancer, with multiple pathways driving its growth and proliferation. GBM often has multiple tumor mutations that make it resistant to treatment.

To effectively treat GBM doctors are going to have to be able to combine multiple therapies, using guidance from DNA, and administer them without toxicity such that they are able to enter the brain and destroy the GBM tumor cells without killing the patient. There are multiple layers of challenges here and many of the technologies needed to overcome them have yet to be developed. I believe and I hope that given time, and money, even these challenges can be overcome.

Postscript

Randy’s Club was formed to keep the memory of my father, Randy, alive and to improve the quality of life of other cancer patients. Visit www.randysclub.org to learn more about us an our products.

References

1. National Brain Tumor Society: Quick Brain Tumor Facts. Available at http://braintumor.org/brain-tumor-information/brain-tumor-facts. Accessed

2. U.S. Food and Drug Administration: cobas EGFR Mutation Test v2. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm504540.htm.