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Targeting Brain Cancer

Researchers are trying to understand brain cancer at the molecular level. Their goal is to find new, more effective therapies for this hard-to-treat disease. By Stephen Ornes
<span style="font-family:helvetica, arial, sans-serif;font-size:10px;font-style:italic">​​​​​​​</span><span style="margin:0px;padding:0px;font-size:10px;border:0px;outline:0px;vertical-align:baseline;background-image:initial;background-position:initial;background-size:initial;background-repeat:initial;background-attachment:initial;background-origin:initial;background-clip:initial;font-family:helvetica, arial, sans-serif;font-style:italic"></span><span style="margin:0px;padding:0px;font-size:10px;border:0px;outline:0px;vertical-align:baseline;background-image:initial;background-position:initial;background-size:initial;background-repeat:initial;background-attachment:initial;background-origin:initial;background-clip:initial;font-family:helvetica, arial, sans-serif;font-style:italic">Image © iStock / yodiyim; 123RF / Rostislav Zatonskiy​</span>
​​​​​​​Image © iStock / yodiyim; 123RF / Rostislav Zatonskiy​

Seven years after her brain cancer diagnosis, Liz Salmi decided she wanted to know more about the makeup of the tumor that changed her life.

Knowledge Empowers Patients​
Ask your doctor about genomic testing.
Salmi had already undergone two surgeries to remove the grade II astrocytoma, an invasive but usually slow-growing brain tumor. After her second surgery, she was treated with Temodar (temozolomide), a chemotherapy drug, for two years. But Salmi, who was 29 when she was diagnosed in 2008, knew her cancer could not be cured. She wanted to be ready when it returned. “I’m living with a brain cancer, and I keep up with what’s going on,” says the 38-year-old communications specialist, who lives in Sacramento, California.
 
In 2015, Salmi read about powerful genomic sequencing tools that made it possible to analyze tumor tissue—peeking inside brain cancer cells and looking for the genetic drivers of the disease. Many experts were arguing that tumors should be classified not only by their appearance under a microscope—the traditional approach—but also according to the presence of certain genetic changes. 

When Salmi first learned she had brain cancer after a series of debilitating seizures in the summer of 2008, this kind of molecular information wasn’t widely available to patients. “I almost feel like I was diagnosed in the Stone Age,” she says. But when the technology became more widespread, she wanted to know what molecular analysis could reveal about her tumor. She approached her neuro-oncologist, who cautioned her to think about her request for a few months. 

“Once you know something, you can’t unknow it,” Salmi says, explaining her doctor’s concern. The results of tumor sequencing, for example, might suggest a favorable or an unfavorable prognosis. Or they could provide no meaningful information at all. Still, Salmi was curious. “The best way for me to cope was to know everything possible,” she says.

Understanding the molecular changes that drive brain cancer remains “potentially transformative,” says Paul Mischel, a cancer biologist and neuropathologist at the Ludwig Institute for Cancer Research in San Diego. Molecular biomarkers can help predict a brain tumor’s likely response to the chemotherapy drug Temodar. This testing can also help assess the risk that a tumor will grow and spread, and can reveal certain genetic variants in the tumor that may respond to experimental treatments. However, genomic testing of brain tumors has yet to uncover ways to extend survival beyond that provided by standard treatments. 

Why the Head Is So Hard
More than 80,000 people in the U.S. are diagnosed with some type of brain tumor each year; of those tumors, about a third are malignant. Brain tumors are usually diagnosed following the onset of troubling symptoms, such as seizures, nausea, vomiting, drowsiness or memory problems. 

Astrocytoma, Salmi’s tumor type, is a glioma. The most common type of brain cancer, gliomas originate in glial cells, which surround neurons in the brain. Gliomas are graded from I to IV. The most aggressive type is grade IV, called glioblastoma, which has the worst prognosis. The median survival after a glioblastoma diagnosis is around 15 months, a number that has barely budged in the past 50 years.
 
Compared to treatment advances for other types of cancer, progress in treating brain cancer has been frustratingly slow. The U.S. Food and Drug Administration (FDA) has approved 16 targeted therapies for lung cancer, 15 for breast cancer and seven for colon cancer, but only one—Avastin (bevacizumab)—for malignant brain tumors. And there’s no evidence that Avastin extends survival longer than chemotherapy and radiation, though it may delay symptoms and extend the time it takes for a tumor to grow.  

Targeted drugs and immunotherapies that have generated excitement by extending survival in some patients with other cancer types have largely failed in clinical trials for brain cancer patients. “Brain tumors do not respond to a lot of the treatment strategies that we try to impose on them,” says Eric T. Wong, a neuro-oncologist at Beth Israel Deaconess Medical Center in Boston. 

There are a number of reasons for this, he says. First, heterogeneity: Brain cancer tumors contain a staggering mix of cells with different mutations, not only from person to person but within a single tumor. That means a treatment that targets one type of mutation might be ineffective against cells in the tumor with a different set of mutations. A treatment-resistant tumor could be the result. “The cells that are most likely to be resistant are the ones most likely to thrive,” says Mischel. 

Then there’s the hurdle of location. Even though brain cancer rarely spreads to other parts of the body, brain tumors such as gliomas can extend like tendrils into surrounding brain tissue. Thus, even the best surgical resections can’t remove all the cancerous cells from the delicate tissue of the brain. 

In addition, “the barrier to the brain is tightly controlled,” says Mischel. This blood-brain barrier, which blocks foreign substances in the blood from entering the brain, can also impede cancer treatment. Chemotherapy, which is often given orally or intravenously after surgery to patients with fast-growing brain cancer, may not even get to a brain tumor because of the barrier. In the same way, targeted drugs that seemed promising in lab and animal studies on brain tumors may not improve survival in patients in clinical trials because they never reach the intended target, Mischel says. 

In other cases, a clinical trial may benefit a small subset of patients and be declared a failure, halting development, because the drug didn’t benefit enough people. “Clinical trials [in brain cancer] usually fail,” says Mischel. “There’s a real emphasis in really thinking hard about an alternate way of doing clinical trials with cancers in the brain.”

Molecular analysis offers one way to rethink clinical trials and to help identify patients who might benefit from a given drug. The National Cancer Institute’s MATCH trial, for example, tests targeted drugs on patients based on their tumors’ genetic characteristics, rather than a cancer site.
 
Brain cancer has been the focus of intense genetic studies in Europe, Canada and the U.S. In 2006, glioblastomas were selected as one of the first tumor types to be studied as part of The Cancer Genome Atlas (TCGA), a 10-year sequencing effort to characterize the genomes of more than 20 tumor types.

“The TCGA really opened up the field,” says David Arons, CEO of the National Brain Tumor Society and chair of the National Cancer Institute’s Council of Research Advocates. “It allowed us to look under the hood of glioblastoma. If you can understand how the engine works and fits together, maybe you can understand how to stop the engine of tumorigenesis.”

The Impact on Patients
Investigations into brain tumors’ genetic machinery have produced some insights. A 2005 study by European and Canadian cancer research foundations, for example, found that the chemotherapy drug Temodar was more effective in treating glioblastoma patients with tumors whose MGMT gene had been switched off. In another advance, researchers showed that in low-grade gliomas, mutations in genes called IDH1 and IDH2 are associated with longer survival and less aggressive disease. Tumors without these mutations are more likely to grow and spread.

01/03/2018
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