Nav: Home

Cognitive decline -- radiation -- brain tumor prevented by temporarily shutting down immune response

November 13, 2018

Treating brain tumors comes at a steep cost, especially for children. More than half of patients who endure radiation therapy for these tumors experience irreversible cognitive decline, a side-effect that has particularly damaging consequences for younger patients. Up to now, scientists had been unable to test potential strategies to prevent this problem because there were no laboratory models that faithfully captured the clinical lifecycle of brain tumors.

But in a new study published Nov. 13 in the journal eLife, UC San Francisco scientists report the first animal model of glioma -- the most aggressive and most common form of brain cancer in the U.S. -- that can also be used to study the long-term effects of radiation therapy in tumor-bearing brains. Using this mouse model, the researchers showed that a drug that temporarily suppresses a key component of the brain's immune system can prevent radiation-associated cognitive decline.

The Cost of the Cure

The National Cancer Institute estimates that there will be nearly 24,000 new cases of brain cancer this year. According to Professor of Neurological Surgery Nalin Gupta, MD, PhD, radiation therapy is among the most common treatments for these malignancies, but it exacts a tremendous toll.

"Radiation treatment has a significant effect on cognitive function in both children and adults," said Gupta, chief of pediatric neurological surgery at UCSF Benioff Children's Hospital and co-senior author of the new study. "However, age plays a major role and radiation has a much more severe effect on young kids."

Earlier studies have found that young children may experience an eight- to 12-point drop in IQ in the years following radiation treatment. These patients may also exhibit conspicuous changes in behavior.

"If you talk to these kids, they'll speak to you normally," Gupta said. "But they'll have substantial problems with problem solving, retention of long-term memories and executive function. Some show behavioral abnormalities as well -- impulsiveness, acting out and bad temper."

To figure out why radiation therapy leads to cognitive impairment, Gupta teamed up with UCSF neuroscientist Susanna Rosi, PhD, an expert on the neurological effects of radiation who previously developed mouse models to study how cosmic radiation affects astronauts.

Radiation Turns Immune System from Friend to Foe

Prior work from Rosi's lab found that exposing mice to radiation led to activation of the brain's immune system -- in particular, a type of cell known as microglia.

"When the brain's immune system is activated by an insult, like radiation, we generally see that microglia start to affect synapses," said Rosi, professor in the Departments of Physical Therapy and of Neurological Surgery and co-senior author of the new study.

But in mice, the same insult that activates the immune system can also cause it to go haywire.

"Activation of the immune system after an insult like radiation is initially protective," said Rosi. "But with time, instead of resolving, the activation persists and becomes deleterious to the neurons."

In these cases, microglia continue to surveil the brain but no longer limit their search to damaged areas. Instead, they begin to attack healthy brain structures, which results in cognitive impairment. The researchers thought that radiation therapy for brain tumors might be launching the immune system into overdrive in a similar way.

A New Model Emerges

Both the presence of glioma and exposure to radiation are known to activate the brain's immune system, so nobody knew whether immune cells would respond to radiation in the same way in tumor-bearing versus tumor-free brains.

"What we wanted to do in this paper is model what actually happens in patients with brain tumors when you treat those patients with radiation. To do this, we had to develop a mouse model of glioma that recapitulates what occurs in the clinic from the onset of the disease through radiation treatment and beyond," said Gupta, a member of the UCSF Helen Diller Family Comprehensive Cancer Center.

Though mouse models of brain cancer were already available, they harbored an intrinsic flaw: in order to introduce cancer into most mice, researchers have to shut down their immune systems. But given that the immune system plays a major role in both the glioma microenvironment and the brain's response to radiation, models that relied on these so-called immunocompromised mice would not suffice.

Gupta and Rosi devised a way to introduce gliomas into mice without shutting off their immune systems by choosing glioma cells and mouse strains with identical immune profiles, thus allowing the cancer to take hold in immunologically normal mice. Using this model, they were able to study the tumor's biology during and after treatment using a system that more accurately reflects what occurs in the clinic.

Radiation, Not Cancer, Impairs Cognition

Prior to this study, scientists didn't know whether tumors contribute to the cognitive deficits observed in cancer patients, or whether the effects arise solely from irradiation. To probe this question, the researchers performed novel object recognition (NOR) tests -- a way to test for cognitive deficits -- on two groups of glioma-bearing mice, one that received no radiation treatment, and one that did.

The NOR tests demonstrated that only the irradiated mice had problems forming new memories; the tumor itself seemed to have no effect on cognitive abilities, and Rosi said her previous research suggests an explanation.

"The hippocampus -- the brain region in rodents and humans that's involved in forming new memories -- is more sensitive to radiation injuries," she explained. "We've used other tests that relate to other cortical structures, and the animals are not impaired. Radiation seems to specifically injure the brain region involved in learning and forming new memories."

A Drug Prevents Cognitive Damage

After establishing that the treatment -- not the disease -- caused cognitive impairment, the researchers figured out how to prevent the immune system from damaging parts of the brain after radiation therapy.

Rosi's lab had previously shown that a compound called PLX5622, developed by Berkeley, Calif.-based Plexxikon Inc., prevents cognitive damage when administered prior to irradiation. The compound acts by inhibiting a receptor in the brain called CSF-1R, which normally activates the brain's immune system after an injury.

"By using this compound to deplete the immune system at the time of irradiation and allowing it to repopulate on its own afterwards, microglia are no longer primed to alter synapses. If we do this, we can prevent neuronal damage and consequently, prevent the cognitive deficits that develop over time after irradiation," Rosi said.

The researchers administered this compound to tumor-bearing mice prior to radiation treatment and found that they could shrink the tumor without impairing cognition -- a result with profound clinical significance if it could be replicated in human patients.

"Ideally, we'd be able to provide this compound to patients prior to their scheduled treatment and prevent cognitive deficits form forming in the first place," Gupta said, adding that he and Rosi hope to move this work into clinical trials.

Another Plexxikon compound that also targets CSF-1R is now being tested in several clinical trials, said Gupta, "and once a drug has completed Phase I trials for another disease, it's relatively easy to get approval to repurpose it for a separate use if you have evidence of its efficacy -- which is what we hope our research can provide."
Authors: Additional authors on the paper include Xi Feng, PhD, Sharon Liu, and David Chen, MD, MPH. Susana Rosi, PhD, is also a member of the Weill Institute for Neurosciences and the Kavli Institute of Fundamental Neuroscience.

Funding: Gupta's research is supported in part by an Institute Award to UCSF from the Pediatric Brain Tumor Foundation. Rosi's research is supported in part by National Cancer Institute Grant R01CA213441.

Disclosures: The authors declare no conflicts of interest.

About UCSF: UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals - UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland - as well as Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children's Physicians and the UCSF Faculty Practice. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. UCSF faculty also provide all physician care at the public Zuckerberg San Francisco General Hospital and Trauma Center, and the SF VA Medical Center. The UCSF Fresno Medical Education Program is a major branch of the University of California, San Francisco's School of Medicine. Please visit

University of California - San Francisco

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Meditations on Loneliness
Original broadcast date: April 24, 2020. We're a social species now living in isolation. But loneliness was a problem well before this era of social distancing. This hour, TED speakers explore how we can live and make peace with loneliness. Guests on the show include author and illustrator Jonny Sun, psychologist Susan Pinker, architect Grace Kim, and writer Suleika Jaouad.
Now Playing: Science for the People

#565 The Great Wide Indoors
We're all spending a bit more time indoors this summer than we probably figured. But did you ever stop to think about why the places we live and work as designed the way they are? And how they could be designed better? We're talking with Emily Anthes about her new book "The Great Indoors: The Surprising Science of how Buildings Shape our Behavior, Health and Happiness".
Now Playing: Radiolab

The Third. A TED Talk.
Jad gives a TED talk about his life as a journalist and how Radiolab has evolved over the years. Here's how TED described it:How do you end a story? Host of Radiolab Jad Abumrad tells how his search for an answer led him home to the mountains of Tennessee, where he met an unexpected teacher: Dolly Parton.Jad Nicholas Abumrad is a Lebanese-American radio host, composer and producer. He is the founder of the syndicated public radio program Radiolab, which is broadcast on over 600 radio stations nationwide and is downloaded more than 120 million times a year as a podcast. He also created More Perfect, a podcast that tells the stories behind the Supreme Court's most famous decisions. And most recently, Dolly Parton's America, a nine-episode podcast exploring the life and times of the iconic country music star. Abumrad has received three Peabody Awards and was named a MacArthur Fellow in 2011.