‘Four Diamonds is absolutely instrumental for testing novel ideas’

Four Diamonds support brings new pediatric cancer researchers to Penn State College of Medicine

Editor’s Note: Penn State’s THON Weekend is Feb. 19-21. Students will dance for 46-hours to support pediatric cancer patients. To date, $127 million has been raised and donated to Four Diamonds, a foundation that supports the families of pediatric patients at Penn State Hershey Children’s Hospital, and the cancer research done here. For more information on THON, or to watch the activities live, visit THON.org. For more information on Four Diamonds, visit FourDiamonds.org.

Their journeys started halfway around the world, but their shared passion for uncovering the causes of pediatric cancer brought them to Penn State College of Medicine. Dr. Wei Li is originally from Peking, China, and Dr. Vladimir Spiegelman is originally from Moscow. Now both are in Hershey, through funding from Four Diamonds, working to understand how pediatric cancers develop in the hopes of discovering new lifesaving therapies.

Dr. Li, assistant professor in the Departments of Pediatrics and Biochemistry and Molecular Biology, came from Memorial Sloan Kettering Cancer Center in New York City. Dr. Spiegelman, Pan Hellenic Dance Marathon Endowed Chair in Pediatric Oncology and professor in the Department of Pediatrics, was most recently at University of Wisconsin.

Dr. Li’s commitment to pediatric cancers was sparked in 2008, when he attended a research conference on a type of nervous system cancer called neurofibromatosis. For the first time, he spoke with teenagers diagnosed with cancer.

“They talked to me about how they were fighting the disease, how they felt about their cancer and what they hope the research could do for their disease,” he says. “I was so impressed with them, and I decided then that I wanted to continue this research when I finished my training.”

Today, Dr. Li is working to understand the underpinnings of brain tumors, which make up about 20 percent of pediatric cancers.

“Brain tumors account for a significant portion of human cancers, especially in children,” he says, “and they are inherently serious and life-threatening.”

The researcher’s work focuses on gliomas, a major class of brain tumors that develop from the supportive tissues in the brain.

Despite major advances in neuroimaging and neurosurgical techniques over the past decades, managing brain tumors with surgery is still a huge challenge for doctors. Sadly, children with glioblastoma, the most aggressive form of glioma, survive an average of only 12 to 17 months.

“In order to radically alter the clinical course of these tumors, it’s important to develop targeted therapies based on cancer cell mutations and the signaling pathways that drive their development and sustain their maintenance,” Dr. Li says.

One cancer pathway that’s of particular interest to Dr. Li is the Hippo tumor suppressor pathway. This pathway is turned off in multiple human cancers, and it may help explain why some cancers are resistant to therapy.

“We hypothesize that a substantial class of glioma arise from mutations that inhibit the Hippo tumor suppressor pathway,” Dr. Li says.

Funding from Four Diamonds gave Dr. Li the ability to set up a lab at Penn State College of Medicine with a team of four researchers and the equipment they need to study the Hippo pathway.

Now that he’s settled in, he’s homing in on a protein called YAP that promotes an oncogenic gene-expression program when the Hippo tumor suppression pathway is defective, allowing cancer cells to survive and grow out of control. Normally, YAP is limited to certain regions of the brain, but the protein is found in a variety of human brain tumors, especially in aggressive gliomas, and high expression is associated with reduced survival rates. If a cause-and-effect association pans out, “YAP could be a new therapeutic target for brain cancers that affect children,” Dr. Li says.

Dr. Spiegelman is also developing new targets for pediatric cancer therapy. He’s investigating why normal genes called proto-oncogenes sometimes turn into cancer-causing “bad” genes called oncogenes. Proto-oncogenes help cells grow, but when they stay active for too long, or when the level is high, they become oncogenes. Oncogenes make cells grow out of control, causing cancer.

More specifically, Dr. Spiegelman’s lab is exploring the role messenger RNA (mRNA) degredation, in the progression of proto-oncogenes into oncogenes involved in pediatric cancers such as neuroblastomas and acute lymphoblastic leukemias. Certain mRNA normally degrades quickly, but when these short-lived genetic messengers are stabilized, they take the brakes off proto-oncogenes.

“One of the ways proto-oncogenes can be oncogenes—drivers of cancer—is by increasing their amount,” Dr. Spiegelman says. “We’re studying why there are a lot of proto-oncogenes in pediatric cancer cells, and why they’re misregulated. If we know more about how they develop, and how we can target them better, we can treat the cancers better.”

His work wouldn’t be possible without Four Diamonds and THON.

“The Four Diamonds Fund brought me here to Penn State because it gave me an opportunity to apply what I had learned about adult cancer to pediatric cancer,” Dr. Spiegelman says. “THON, which supports Four Diamonds, allows us to pursue avenues that otherwise wouldn’t be funded—more risky approaches that the federal government or other agencies will not fund until there’s a substantial amount of preliminary data to support it. Four Diamonds is absolutely instrumental for testing novel ideas.”

Building on his years of research, Dr. Spiegelman has already identified a novel target for therapy for pediatric cancers, and he’s working on identifying drugs that can affect it.

Like Dr. Li, he’s inspired to help children who are battling cancer.

“Cancer research in general is not only fascinating, but it’s a noble cause to help humanity,” he says. “The desire to cure this group of diseases is what drives me to go to work every day, and to cure this group of diseases in children makes it an even nobler cause.”

-Jennifer Abbasi

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