New research suggests combination therapy to battle aggressive brain tumors

by Tim Bonfield

Qing Richard Lu, PhD.

Qing Richard Lu, PhD

The thing about treating brain tumors is that too many of them fail to stay treated. Medical literature is riddled with examples of promising chemotherapies that initially shrink tumors, but then the cancer adapts and comes roaring back.

Now an international research team, led by scientists at Cincinnati Children’s, may have found a way to overcome the problem of rapid drug resistance. The latest findings specifically address an aggressive form of medulloblastoma, one of the most common forms of brain cancer in children. However, the work suggests an approach that may have wider impact.

The team discovered a novel tumor suppressor gene in medulloblastoma, and showed that Rolipram, a cellular cAMP-elevating agent and antidepressant approved for use in Europe and Japan, also has the ability to suppress brain tumor formation in mice. Detailed findings were published online Aug. 24, 2014, in Nature Medicine.

Qing Richard Lu, PhD, scientific director of the recently formed Brain Tumor Center at Cincinnati Children’s, was the lead investigator. The study included collaborators from nine medical centers in four countries.

“Although current treatments improve survival rates, many patients develop relapse tumors carrying mutations that resist treatment,” Lu says. “This underscores an urgent need for alternative targeted therapies.”

A PATHWAY TO A CURE?

With the rapid growth of whole-genome sequencing techniques, scientists are learning more about how and why the body’s normal defenses against cancer break down. One line of defense begins with the gene GNAS. In healthy people, this gene encodes the Gas protein, which in turn kicks off a molecular signaling cascade that suppresses tumor growth. Mutations disrupting this pathway can lead to rapid cancer cell growth.

Lu and his colleagues uncovered the GNAS connection to medulloblastomas by finding a mutation in a sample from a child’s tumor. Existing medical literature revealed that the gene’s function could be influenced by the antidepressant medication Rolipram.

Lu and colleagues studied this pathway using a line of mice that do not express the GNAS gene. These mice developed brain tumors, as expected, but when given the drug Rolipram, the tumors shrank. The researchers believe the drug restores the Gas pathway’s tumor suppressing power by elevating levels of a signaling molecule called cAMP. Better still, the treatment appears to help against even the toughest tumors.

“Many chemotherapies become ineffective as soon as the surface receptors they target change, but this drug may help to get inside the cells targeting a signaling juncture downstream to overcome the drug resistance,” Lu says.

The Rolipram findings reflect only one drug affecting one part of the Gas signaling pathway. Lu and colleagues are working to identify all of the other genes and related markers along the pathway. It may be that other drugs acting at other points will prove even more effective.

In the image of a mouse brain below, actively dividing cancer cells appear in red.

Dr. Qing Richard Lu says the antidepressant Rolipram has potentially strong tumor suppressing power, especially against an aggressive form of medulloblastoma. In the image of a mouse brain below, actively dividing cancer cells appear in red.

CHILDREN NEED KID-FOCUSED DRUGS

The medulloblastoma study is one of the first important findings from a growing team of brain tumor researchers at Cincinnati Children’s. Lu arrived in Cincinnati about a year ago from the University of Texas Southwestern Medical Center in Dallas. As scientific director of the Brain Tumor Center, he works with a loosely affiliated group of more than 15 scientists here who are using whole-genome sequencing and other methods to reveal why brain tumors form and how they can be stopped.

Finding precise ways to target cancer cells is especially important for treating children with brain cancer, Lu says. Several adult chemotherapies are designed to target rapidly dividing cells, which stand out as tumor markers once the adult brain is fully formed. In children with brain tumors, healthy brain cells are dividing and multiplying right alongside the cancerous ones. Simply targeting dividing cells can harm a child’s developing brain.

“Pediatric brain tumors are quite different than adults. Genome sequencing shows that they use different mechanisms to initiate tumor formation,” Lu says. “So pediatric cancers need to be targeted in different ways.”

The next step for the follow-up study will be to prepare for a clinical trial with different cAMP-raising agents. Findings that look hopeful in mice often do not work as well in humans, so it remains too early to tell how many children, if any, could be helped by a Rolipram-chemo combination therapy. Regardless, Lu sees the findings as a proof of concept. Even if Rolipram, or analogs thereof, do not work, other promising treatments will emerge by following a similar gene-disease-drug search process.

“By studying brain tumors in children with whole-genome sequencing, we will have a better chance of finding the mutations that really cause the cancer,” Lu says. “In adults, we can find many mutations, but it is unclear which ones are crucial for initiating tumor formation. It will still take a few more years, but as we identify more tumor-causing factors, this will lead to more effective treatments with fewer risks of side effects.”