Pediatric cancer research thriving thanks to Four Diamonds

August 16, 2017 at 12:28 pm Leave a comment

By Jade Kelly Solovey

While outcomes for children diagnosed with cancer have improved greatly over the past five decades, one-in-five children will still die from their disease. In the United States, more children die from cancer than any other disease.

Investigators at the Four Diamonds Pediatric Cancer Research Center at Penn State Children’s Hospital are working to change that.

Four Diamonds supports more than 80 pediatric cancer research professionals who are working to identify more effective therapies that increase cure rates and minimize long-term side effects by studying how cancer forms and developing new targeted treatments.

“With Four Diamonds support we have been able to continually expand our research,” said Dr. Barbara Miller, division chief, pediatric oncology and hematology and director of the Four Diamonds Research Center. “We conduct laboratory based research to better understand disease mechanisms in pediatric cancer and to identify potential targets in the molecular disease process to which new drugs can be directed.”minithon

Funding from Four Diamonds has helped finance development of a Pediatric Neuro-oncology Program, a Pediatric Cancer Survivorship Program, a Stem Cell Transplant Program, an Experimental Therapeutics Program, a fellowship training program, as well as the Research Center itself.

The money raised for the Clinical Experimental Therapeutics Program allows investigators to conduct phase one and phase two trials for pediatric cancer patients.

“These are very early trials with new drugs to treat patients whose disease is resistant or refractory to any of the existing therapies,” Miller said. “Because of this program, we can offer these very exciting new treatments here in central Pennsylvania so patients do not have to travel a distance.”

Additionally, these new therapies are often not available to patients until phase 3.

Investigators at the Four Diamonds Pediatric Cancer Research Center are members of the Children’s Oncology Group, Pediatric Oncology Experimental Therapeutics Investigators Consortium and the Neuroblastoma and Medulloblastoma Translational Research Consortium.

Working with these organizations gives patients access to new drugs and novel therapeutic approaches for cancers which are difficult to treat. For example, one of the consortium trials offers an individualized approach to treatment of refractory cancers tailored to each patient.

“We are currently developing an adolescent and young adult oncology program because for a number of cancers, adolescents and young adults have been shown to do better when treated with pediatric rather than adult regimens,” Miller said. “We’re working out how to provide the best care for these patients.”

The support from Four Diamonds has allowed for recruitment of outstanding research talent.

“With these endowments, we’ve been able to develop a formidable group of scientists. All of the investigators are looking at different aspects of molecular signaling pathways that lead to tumor development and are working on drugs targeted to those pathways,” Miller said.

Miller’s own research concentrates on a channel highly expressed on the surface of many pediatric tumors including neuroblastoma and leukemia. This calcium channel protects cells from being destroyed and also controls the cell’s energy production.

“We’re exploring how it does that with the hope that in the future we can target it to reduce the ability of cancer cells to grow and survive, particularly to reduce survival after chemotherapy,” Miller said.FourDiamonds_Logos1

Dr. Sinisa Dovat, director of Therapeutics and Translational Research, and his team have several innovative projects in the works.

One is trying to understand what makes leukemia cells multiply and how cell proliferation is regulated so that more efficient, specific and less toxic treatment can be designed.

According to Dovat, B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer.

“Pediatric leukemia is the most common malignancy. At the same time, it’s had the biggest success and the least success,” he said. “We went from 0 percent survival in the 1950s to 90 percent today, this is one of the biggest successes in medicine. On the other side, with relapsed leukemia, survival is still 50 percent and that has not changed over the last 30 to 40 years.”

His study concentrates on the Ikaros protein, a molecule that impedes and suppresses the development of leukemia cells.

fdOne of Dovat’s published studies involves a drug that can restore the function of Ikaros and effectively suppress leukemia. Further study will be required to determine other medications that can be combined with this drug to treat B-ALL.

“We can combine the drug with additional medications in a rational, targeted way because one single drug cannot cure malignancy, and one single malignancy cannot be cured by one single drug,” he said.

Dovat’s team has also delved into system biology — epigenetics — an emerging science. While genomics is the study of DNA, epigenetics is the study of the biological mechanisms that switches genes on and off, making some genes active while others remain inactive.

“We are studying the epigenetics of cancer cells to see how these changes in the cell affect cell multiplication in leukemia,” he said.

According to Dovat, this is a rapidly developing area of study. His lab and other labs across the country have already made significant progress and have developed drugs that target specific epigenetics.

Dovat believes funding from Four Diamonds is essential to the advancement of pediatric cancer research.

“Based on these results, we’ve received additional funding from other organizations. Once you get the preliminary data and you publish that information that of course attracts more money. Four Diamonds support helps us do the groundwork to take our research to the next level,” he said.

That includes funding from the National Institutes of Health (NIH). Each of the Four Diamonds Research Center’s investigators are NIH funded, which is an extremely competitive application process.

“Four Diamonds support of initial steps in childhood cancer research has allowed us to receive national recognition for our work and to have all Four Diamonds  investigators currently NIH funded is a  real achievement these days, especially with very low NIH funding rates ” Miller said.

Dr. H.G. Wang, director of pediatric molecular oncology, believes that teamwork is the key to fighting cancer.

“Teamwork is not only among the scientists, but between the scientists, the physician, the patient and also society,” he said. “Then we can find a potential new treatment and eventually find a cure. By getting society involved, we can start to prevent cancer. Scientists try to learn more details about the mechanisms, and hopefully we can translate the basic research discovery to the hospital setting and help more patients.”

The process to take a therapy from the lab to the bedside requires tremendous patience.

In order to get a new drug through the FDA for approval it normally takes 10-12 years at an average cost of $2.7 billion.

“It’s a long process and very, very costly,” Wang said.

Wang believes that is one of the important reasons for Four Diamonds.

Pediatric and adult cancers are very different diseases and the pediatric cancer market is much smaller than the adult market.

“That’s why a lot of pharmaceutical companies don’t want to invest too much because it’s too costly. They don’t see a big market down the road to make a return on their investment,” he said.

Because of this, pediatric cancer drug development is behind.

“That’s why we not only need government support, but we also really need philanthropic support through Four Diamonds to do more and better research to develop new treatment strategies,” Wang said.

While childhood cancers are often genetic, causes of adult cancers are often environmental, hormonal, due to poor life style choices or related to aging, according to Miller.

“Often what happens in adults is that over time, environmental and other factors they’re exposed to cause genetic mutations. These accumulate in tissues and cells and ultimately can lead to the uncontrolled cell growth that is cancer,” she said.

Additionally, Wang said because of the differences in pediatric and adult cancers, a treatment or a drug for an adult’s leukemia may not work for a pediatric leukemia patient.

The current focus of Wang’s team’s research is autophagy, the self-eating process of a cell.

“The cell generates a lot of garbage. Just like we would recycle a can or bottle for reuse, the cells can collect all of this trash and generate a new building block,” he said.

This kind of self-cleansing process is very critical to keep the cells healthier and the tissue more functional.

Its role in cancer is truly complex.

“Autophagy can prevent a DNA mutation and also the transformation of normal cells,” Wang said. “It’s a housekeeping system to clean up all of these harmful materials.”

On the other hand, autophagy also is critical for cancer cell survival. The process generates nutrients the cells need.

“The question is how autophagy can affect the cancer cells’ survival and how this affects the cancer cells’ response to treatment,” he said.

“The data suggests that we may be able to use autophagy to kill cancer cells.”

This should make cancer cells more vulnerable to the treatment.

The team has more work to do in the area of genetics to better understand how and why the cells react the way they do. They also hope to identify new compounds to target autophagy for the treatment of pediatric cancers.

Dr. Miller emphasizes “The investigators at Penn State are forever grateful to Four Diamonds and those who support it. These funds are key to our ability to do innovative research to develop new therapies. They provide support for the infrastructure to conduct clinical trials to increase our ability to cure more children and to reduce long term side effects in those who are cured. Four Diamonds enables us to give our patients HOPE.”

For more information on Four Diamonds and pediatric cancer research, visit


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