Accelerating Progress in the Treatment of Glioblastoma Multiforme

A Conversation With W.K. Alfred Yung, MD


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W.K. Alfred Yung, MD

W.K. Alfred Yung, MD

W.K. Alfred Yung, MD, has wanted a career in medicine since he was a high-school student and has spent nearly 4 decades fulfilling that dream, specifically in the research and treatment of one of the deadliest cancers, malignant brain tumor, especially glioblastoma multiforme, the most common brain tumor. According to the National Brain Tumor Society, brain tumors killed about 17,000 people in the United States in 2016.1

Dr. Yung has spent the past 35 years at The University of Texas MD Anderson Cancer Center in Houston, where he was recruited in the early 1980s to build the center’s first neuro-oncology department and currently serves as the center’s Professor of Neuro-Oncology and Cancer Biology and is a member of MD Anderson’s Glioblastoma Moon Shot Initiative. During those years, he has seen frustratingly slow progress in the survival rates for people with glioblastoma—doubling from 9 months to 18 months.

Now, he said, advances in genomic sequencing; new technology such as liquid biopsy, which can detect early-stage cancer, identify tumor-associated mutations, and monitor disease progression; and a greater understanding of the biology of brain tumors offer the potential to accelerate progress in this cancer. He cautions, however, that to turn that potential into reality will take increased research funding and a more team-science approach to research in brain tumors.

In November, MD Anderson Cancer Center announced the creation of the Beau Biden Chair for Brain Cancer Research in memory of Vice President Joe Biden’s son, Beau Biden, who died of glioblastoma on May 30, 2015. The Biden Chair also honors Dr. Yung, who was Beau Biden’s physician, for his work in brain cancer research and patient care. In addition to his position at MD Anderson, this past July, Dr. Yung was named Special Advisor to the Chief Executive Officer of the National Brain Tumor Society, where he is guiding new and ongoing research and science policy in brain tumors and is an executive committee member of the Adaptive Global Innovative Learning Environment (GBM AGILE), an international adaptive trial in glioblastoma.

In a wide-ranging interview with The ASCO Post, Dr. Yung discussed the progress being made in the treatment of brain tumors and how that progress can be accelerated to increase survival for people with this fatal cancer.

Progress Still Needed

Why has the median survival for patients with glioblastoma multiforme remained at less than 18 months over the past 3 decades?

Although we have made some progress in this cancer and have made patients’ lives better, survival is still too short. The reasons are many. First, we are dealing with a complex and heterogeneous disease that makes treating it difficult, and the complexity of the disease, plus its location in the brain and proximity to the cranium, adds another clinical barrier its treatment as well as treatment side effects. As a result, it has been a major challenge for us to overcome and to make progress in this cancer.

Promising Research Areas

What are the main areas of promising research in brain cancer, and what do you see happening over the next 3 to 5 years?

Our number-one focus is on understanding the biology of this cancer better, its heterogeneity, its multiple overlapping growth and invasion pathways, and its microenvironment, especially the immune environment in the brain and in the brain tumor. In the past, we’ve said that the immune environment in the brain is very different from the immune environment in the body, and that still may be true. We just don’t have an understanding of the immune environment in the brain and how it interacts and regulates the growth of the tumor.

Another area of study is the metabolism of the tumor and its interaction with the metabolism of the brain. These issues are critical to overcome not only in finding the right treatment, but also in managing treatment side effects.

We need to propel the translation from research into the clinic in terms of finding the right immunotherapy strategy and developing the right combination of immunotherapy with small molecule therapy, with radiation therapy, and also with the development of metabolic therapies.

Surgical Techniques

Will there also be more precise surgical techniques developed?

Surgical technique improvement is always there. If you look over the past 30 years, much of the improvement in the quality of life for patients with brain tumors has to be attributed to better surgical techniques and more precise surgery, as well as better radiation machines and more precise radiation-directed therapy.

I think this progress will continue. For example, there are more local therapies being developed with radiation therapy, thermal therapy, and ultrasound therapy, and the integration of these different techniques with surgery and radiation therapy will allow for more precise surgical ablations and radiotherapy.

Immunotherapy

You mentioned immunotherapy for brain cancers. Do you think immunotherapy will become a bigger component in the treatment of this disease?

Yes, I do, but there are some issues with immunotherapy. Although there is a lot of enthusiasm for immunotherapy for other solid tumors such as lung cancer, renal cell carcinoma, bladder cancer, and melanoma, the applications of checkpoint inhibitors and T-cell therapy have been slower in the development for brain tumors. We also have a different challenge because of the location of the tumor in the brain, the particular immune environment of the brain, and the development of edema and massive inflammation in the brain from the therapy, all of which cause a different management scheme for the brain vs tumors in other parts of the body, such as the lungs or abdomen.

For example, the goal of immunotherapy with T-cell checkpoint inhibitors is to make the cellular therapy more active, with heightened aggressiveness in seeking out the tumor and bringing more immune cells or inflammatory cells to the tumor bed. That process causes a different kind of issue in the brain than in other parts of the body, because there is not much space for the brain to swell up from the inflammation caused by the treatment vs the same inflammation it causes in the breast or in the lungs, where there is a lot more space for the development of inflammation without causing symptoms. In the brain, there is not much space for swelling without causing immediate neurologic problems, even herniation or death.

Oncolytic Virotherapy

Is excessive inflammation in the brain the issue with the PVS-RIPO poliovirus now being investigated to kill brain tumors?

Yes, inflammation is the issue with all of the oncolytic viruses that are now being studied for brain tumors, including the poliovirus, adenovirus, measles virus, and herpes virus. All four types of viruses are used in oncolytic virotherapy, and they cause the same inflammatory reaction, so the problem is not unique to the poliovirus.

The key with this treatment is to figure out how to manage the inflammatory side effect without destroying the immune and inflammatory cell activity.

Brain Cancer Research

What will it take to accelerate progress in the development of more effective therapies for brain cancers? Increased research funding and a more team-science approach to research?

Yes, both of those things. We need to understand the science better, so we need more fundamental knowledge in the causes and development of these tumors. We need to understand more about the heterogeneity of these tumors and the genetic makeup of the immune system as well as the phenotypic features of the immune system and learn how to hit multiple targets with multimodalities. To accomplish those goals requires more investigators with innovative ideas working together in a team and sharing their information and data—and, of course, that requires more investment of dollars.

If the National Cancer Moonshot initiative is funded, will it provide the atmosphere for the scientific sharing of ideas you are talking about and result in accelerating progress in the development of more effective therapies for brain tumors?

With more talented researchers and clinicians working in neuro-oncology, increased funding, and the cross-disciplinary team-science approach to research, we will conquer all brain cancers in adults and children.
— W.K. Alfred Yung, MD

Yes, I believe so, and I hope it will be funded. I have high hopes that the new administration will continue to support this great goal of making accelerated progress in cancer research. We have many types of cancer that desperately need that progress, including glioblastoma, pancreatic cancer, and hepatic carcinoma, and although they are relatively rare, they kill many patients each year. I lost my sister at age 47 to hepatic carcinoma, just 6 months after she was diagnosed, and I have bladder cancer, and it’s recurrent and metastatic, so we need to accelerate the pace of progress in these difficult cancers without delay.

And even though the Cancer Moonshot Blue Ribbon Panel has done a great job of determining a list of priorities for the National Cancer Institute to fund, we just need to roll up our sleeves and go to work with the funding we currently have.

Potential Therapeutic Targets

What are emerging as potential therapeutic targets for brain tumors?

Thanks to the work of The Cancer Genome Atlas program, we know a lot about the genetic makeup of this disease. We have not translated that knowledge into a winning therapy though, but we are doing better in terms of finding therapeutic targets. The next level of understanding we need is how to combine therapies for maximum effectiveness, because we know that glioblastoma, as opposed to cancers such as leukemia, is not a single hit or a single pathway disease. It has multiple tumor mutations and alterations, and we need to learn how to give appropriate combination therapy with guidance from the biologic genetic data of the tumor and also to give that combination therapy without toxicity and, most important, with drugs that enter the brain. These are multiple-level challenges, but I think we have the technology, the knowledge, and the talent to overcome them. We just need more money.

Liquid Biopsy

What role will liquid biopsy play in the diagnosis of brain tumors, treatment monitoring, and early detection of disease recurrence?

Liquid biopsy will become a very important tool in the diagnosis and treatment of brain tumors, if you consider that the brain is such a delicate organ we cannot afford to damage good brain tissue with invasive surgical procedures for tumor tissue biopsies. We also can’t get to the brain tumor very easily or frequently with conventional surgical methods as you can for cancers such as melanoma or breast cancer.

Research in liquid biopsy is showing that circulating DNA in the blood or cerebrospinal fluid can identify tumor-associated mutations and provide clinically meaningful information about a patient’s tumor before, during, and after treatment. This is huge progress in being able to define and detect new cancer cells and to identify the load of cancer in the brain and early detection of recurrent disease as well as in having a noninvasive means for guiding new treatment options.

The technology for obtaining accurate molecular information from liquid biopsies is already here. It’s just a matter of a better tumor-derived DNA-detection mechanism and validation in terms of when is the best time to perform liquid biopsy in brain tumors. But I think we are very close to adding liquid biopsy to our standard-of-care diagnostic testing in cancer care.

[Editor’s note: On June 1, 2016, the U.S. Food and Drug Administration (FDA) approved cobas EGFR Mutation Test v2, a liquid biopsy test for the detection of non–small cell lung cancer. It is the first liquid biopsy test approved for use by the FDA.2]

Accelerated Phase of Understanding

With all of the complexities of the biologic, genetic, and molecular structure of malignant brain tumors, are you optimistic that it is possible to accelerate progress in this cancer?

Yes, I am optimistic. With the help of the genomic revolution and advancements in genomic-sequencing technology over the past 10 years, we are in an accelerated phase in our understanding of brain tumors, as opposed to the flattened curve we were in previously, and that progress will become even more accelerated in the future. So even though the challenges we face continue to be great, with the combined scientific talents of the United States and the rest of the world, we should be able to make better and faster progress for our patients.

The solution to conquering difficult brain tumor types, including glioblastoma and pediatric high-grade tumor, is not that different from other difficult diseases. We need to attract more scientific and clinical talent to this disease, which traditionally has gone to the big disease types such as breast and lung cancers. With more talented researchers and clinicians working in neuro-oncology, increased funding, and the cross-disciplinary team-science approach to research, we will conquer all brain cancers in adults and children. ■

Disclosure: Dr. Yung is a scientific advisor to the National Brain Tumor Society and DNAtrix.

References

1. National Brain Tumor Society: Quick Brain Tumor Facts. Available at http://braintumor.org/brain-tumor-information/brain-tumor-facts. Accessed December 12, 2016.

2. U.S. Food and Drug Administration: cobas EGFR Mutation Test v2. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm504540.htm. Accessed December 12, 2016.



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