6 things to know about glioblastoma

Following Sen. John McCain’s diagnosis, Fred Hutch experts offer ‘the long view’ on brain cancer research
Sens. Edward M. Kennedy, Joe Lieberman, John McCain
Sen. John McCain, right, said of his old friend and favorite sparring partner, Sen. Edward M. Kennedy, left, "He took the long view. He never gave up." Kennedy, shown here along with Sen. Joe Lieberman, center, died of glioblastoma in 2009. File photo by Rex / Shutterstock via AP

There was something especially poignant about the news that John McCain, the Republican senator who has represented Arizona in Congress for more than 30 years, has been diagnosed with the same aggressive brain cancer that felled another Senate giant, his long-time friend and favorite Democratic sparring partner, Edward M. Kennedy of Massachusetts. Cancer really is bipartisan.

Late Wednesday, McCain’s office released a statement that the former Navy pilot who survived five years as a prisoner of war during Vietnam and twice ran as his party’s candidate for president had glioblastoma. McCain is now reviewing treatment options with his family and care team at Mayo Clinic Hospital in Phoenix, Arizona.

Colleagues from both sides of the aisle, world leaders and ordinary people reacted with an outpouring of supportive emails, tweets, Facebook postings and prayers. McCain’s daughter, Meghan McCain, captured the public mood in her moving personal tribute. “The cruelest enemy could not break him,” she wrote. “The aggressions of political life could not bend him. So he is meeting this challenge as he has every other. Cancer may afflict him in many ways: But it will not make him surrender. Nothing ever has.” 

Glioblastoma is a particularly cruel enemy. Kennedy lived for 15 months after his diagnosis, which is about the median survival time for glioblastoma with treatment. He died in August 2009 at age 77.

McCain, who is now 80, spoke at the funeral. In words that could also describe himself, he praised Kennedy’s “bellowing laughter” and “uncanny sense for when differences could be bridged.” Noting his old friend’s passion for legislating — and life — McCain said, “He took the long view. He never gave up.”

Drawing on experts at Fred Hutchinson Cancer Research Center, here is the long view on glioblastoma diagnosis, treatment and research:

What is glioblastoma?

The most common type of primary brain tumor is called a glioma, so named because it begins in the glial (the Greek word for “glue”), or supportive, tissue of the brain. A glioblastoma is the most malignant form of this tumor and is synonymous with a grade 4 glioma. Glioblastoma is also sometimes called a grade 4 astrocytoma because it arises from star-shaped cells called astrocytes, one of several types of glial cells. According to the American Brain Tumor Association, glioblastomas represent about 15 percent of all primary brain tumors. An estimated 12,390 cases are predicted for 2017.

Sen. McCain previously was treated for melanoma. Is this new tumor related?

No. McCain has had several early-stage melanomas removed, and melanoma can metastasize to the brain. However, a primary brain tumor — as McCain’s doctors described the tumor in the statement released by McCain’s office — forms because of abnormal cell growth in brain tissue rather than spreading to the brain from elsewhere in the body. Melanoma, a deadly form of skin cancer, starts in melanocytes, the cells that give skin its color.

How is McCain’s brain cancer different from former President Jimmy Carter’s cancer?

Carter did have melanoma that had spread to his brain and liver, which he revealed in 2015. Until recently, someone whose melanoma had spread to the brain usually survived for only about four months. However, in 2011, melanoma became one of the first cancers to be treated with immunotherapy. After surgery to remove a small mass from his liver, Carter began receiving an immunotherapy drug called pembrolizumab (Keytruda), one of several “checkpoint inhibitors” that helps free the immune system to attack the cancer. Data from clinical trials show that 50  percent of patients who received penbrolizumab for metastatic melanoma are alive three years later.

What are the treatment options for glioblastoma?

Since 2005, a combination of surgery, chemotherapy, and radiation has been the standard of care for glioblastoma, according to neurosurgeon Dr. Eric Holland, who is director of Seattle Translational Tumor Research and senior vice president and director of the Human Biology Division at Fred Hutch. McCain underwent a minimally invasive craniotomy with an eyebrow incision last week to remove what at first was described as a blood clot and later identified as glioblastoma. According to the statement from his office, further treatment options under discussion include chemotherapy and radiation.

Sadly, this aggressive cancer poses significant challenges to standard treatment, which is why median survival remains stuck at 15 months. (“Median survival” means the time, from diagnosis, at which half of patients are expected to still be alive.)

As Holland explains, glioblastoma is very difficult to completely remove surgically because it is so diffuse in the brain. The blood-brain barrier, which protects the brain and its associated fluid, limits the drugs that can reach tumors, and glioblastoma is resistant even to those drugs that can get in. Brain tissue, and especially brain cancer, is also resistant to radiation.

What about immunotherapy?

In May, a team of Hutch researchers led by Holland began a two-year pilot study to test several novel immunotherapy approaches for glioma.

“The standard of care for patients with these tumors — surgery followed by radiation and chemotherapy — has not changed in decades, and neither has the outcome,” Holland said at the time. “We hope through this work to change the standard of care and prolong survival for glioma patients.”

T-cell therapy, an experimental treatment in which certain immune cells are engineered to recognize and attack tumors and which is showing promise for certain blood cancer patients, is being tested in some small, early-stage clinical trials for patients with glioblastoma at some other research centers. Other types of immunotherapy for glioblastoma also are in early clinical trials.

But it is still early days for these approaches designed to harness or amplify certain components of the immune system. Holland warned that the interplay between cancer and our immune system is complex and much is still to be learned, especially in relation to a cancer as challenging as glioblastoma.

Are there other promising approaches?

Yes. For example, here are four promising avenues of research:

  • The advent of in-depth tumor gene sequencing has given scientists insights into mutations in a gene known as isocitrate dehydrogenase, or IDH, which usually make gliomas significantly less aggressive than gliomas with a normal IDH gene. Median survival of patients with IDH mutations can be five or even 10 years. Holland and his team have developed mouse models that will allow them to study these mutations, which until now has been impossible because the mutant cells will not grow in laboratory dishes. Holland is hopeful that research into the fundamental nature of IDH-mutant glioma cells and their interaction with the immune system will reveal “an Achilles’ heel" for targeted treatments.
  • Holland also is hopeful that precision oncology — which is his area of expertise — can lay the groundwork for better treatments for glioblastoma and other cancers. He and others are collecting data and developing tools that will help researchers and doctors better understand how a patient is likely to respond to a given treatment — whether standard or immunotherapy — and to tailor their care accordingly, he said.
  • Fred Hutch gene therapy experts Drs. Hans-Peter Kiem and Jen Adair are taking a different tack against glioblastoma — using gene editing to protect blood stem cells from a drug that can make chemotherapy more effective against the cancer. Some patients with glioblastoma produce a certain protein in their tumors that make cancer uniquely resistant to chemotherapy. There is a drug that “can unlock the tumor cell to that chemotherapy,” Kiem said in a recent interview, but that drug molecule is very harmful to blood cells. Kiem, who holds the Endowed Chair for Cell and Gene Therapy at the Hutch, and his colleagues developed a workaround: engineering the blood cells in the lab with a gene that shields them from the molecule and then transplant the protected cells back into the patient before proceeding with chemotherapy cycles. Results from a small early clinical trial “look very good,” Kiem said, and he is putting together a larger, multicenter study with two other cancer research centers.
  • After his mother’s death from glioblastoma almost 20 years ago. Dr. Barry Stoddard, a Fred Hutch protein engineer, got involved in a research project to modify a protein from yeast for possible use as part of targeted cancer therapy. The modified protein was the brainchild of Washington State University biologist Dr. Margaret Black, who recognized that with a few tweaks, this natural molecule could have potent anti-tumor power. After years of development and testing in animal models, the engineered enzyme was tested in a small clinical trial for patients with aggressive glioblastoma that was led by a biotech company in San Diego, Tocagen. Recently, the company researchers and their colleagues reported results from that early-stage trial: The enzyme — and the rest of the drug built around it — is safe and maybe extending patients’ lives.

Fred Hutch News Service writers Rachel Tompa, Sabrina Richards and Kristen Woodward contributed to this story.

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Mary Engel is a former staff writer at Fred Hutchinson Cancer Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.

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