Improving the Odds

What is true in gangster movies is true with cancer tumors. The bad guys have bodyguards.

Research by Dr. Kelly Goldsmith, a pediatric cancer specialist at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, is targeting the molecular bodyguards that protect particularly nasty cancer cells.

Neuroblastoma is a cancer that develops in the nerve tissues of the adrenal gland, abdomen, chest and neck. Apart from brain tumors, it is the most common solid tumor among children and about half of neuroblastoma cases are found in children younger than two years old.

The gravity of a diagnosis of neuroblastoma varies according to the tumor’s classification among three risk categories: low, intermediate, and high. A low-risk tumor is highly curable, but high-risk neuroblastoma kills more than half of the children with the disease.

"The majority of those children die from recurrent disease because the cancer becomes resistant to chemotherapy," says Dr. Goldsmith, also an Assistant Professor of Pediatrics at Emory University School of Medicine. "For this tumor, we’ve got to figure out a better way to make the children chemotherapy-sensitive again, or to therapeutically target the tumor without harming normal tissues."

Apoptosis, or programmed cell death, is a method by which cells are eliminated from the body without releasing harmful substances to surrounding normal tissues. Apoptosis plays a crucial role in developing and maintaining health by eliminating old cells, unnecessary cells, and unhealthy cells, like pre-cancerous ones.

Chemotherapy and radiation kill tumor cells by triggering apoptosis. Therefore, many aggressive tumors, including neuroblastoma, have found ways to survive chemotherapy by altering their apoptosis genes.

Neuroblastoma cells depend on certain members of the Bcl-2 family of proteins to protect them from apoptosis. Other members of the Bcl-2 family, called BH3-only proteins, can trigger apoptosis. Research by Dr. Goldsmith has shown that small chains of amino acids—called BH3 peptides—can mimic the BH3 proteins and kill neuroblastoma cells in test tubes and in mice.

Dr. Goldsmith also applied the BH3 peptides to small tumor organelles such as mitochondria. This enabled her to determine which Bcl-2 proteins a tumor depends on for survival.

The goal of Dr. Goldsmith’s research is to develop profiles of tumor cells—breaking them down to the bare essentials—and then use these that information to determine the best drugs to use in treatment.

But establishing the effectiveness against cancer cells in test tubes and live test subjects is just one step along the way to treating children. According to Dr. Goldsmith, the next phase of research requires fresh neuroblastoma tumor tissue.

However, there are many competing demands for the limited supply of tumor tissue. For research efforts to continue, new techniques are needed to reduce the amount of human tumor tissue needed for experiments.

To address this need, Dr. Goldsmith partnered with other researchers in her field to adopt an improved method for screening and selecting human tumor samples that can be used in her research. However, this new method required the use of laboratory equipment that Dr. Goldsmith lacked.

Through generous donor funding, she was able to obtain a BIOTEK multiwell plate reader. This laboratory device is required to carry out the new method of identifying tissue samples. It is also crucial to the many additional experiments and studies that are planned. Says Dr. Goldsmith, "This plate reader has been and will continue to be critical to the experiments [we have] proposed."

The new identification method uses the plate reader to reveal how tumor cells react to BH3 proteins (which protect cells from apoptosis). Based on how the tissues’ cells react to BH3 proteins, each sample is assigned a BH3 response profile. These profiles are used to identify tumor samples that are the best candidates for use in experiments.

The new method has significantly reduced the amount of tissue needed for research. Since the supply of actual human tumor samples is so limited, this is a significant step forward for Dr. Goldsmith’s research efforts. "This technique will also propel the workflow forward for cells in culture," she said, "given that fewer cells are required per BH3 profile."

Now that Dr. Goldsmith has obtained the multiwell plate reader and adopted the new method of screening tumor samples for experiments, she can focus on the next phase of her research. Her goal is to establish how effective the BH3 peptides are against cancer cells in actual human tumor tissues.

By applying the peptides—which mimic BH3 proteins and have been used to kill neuroblastoma cells in test tubes and in live test subjects—to the human cancer cells, Dr. Goldsmith can observe how the peptides and tumor cells interact. She also will combine the peptides with additional drugs that are designed to inhibit tyrosine kinases (proteins that help the cancer cells survive and grow).

Called combination therapy, both of these approaches offer more tumor-specific, less toxic treatments for children with highly chemo-resistant neuroblastoma tumors. According to Dr. Goldsmith, these options "promise a quicker, smoother transition for these and similar agents into clinical trials for children with [chemo-resistant] neuroblastoma."

To further her fight against neuroblastoma, Dr. Goldsmith extended her research into COUP-TF1, which could be a significant biomarker in children with the condition.

 

Having identified that COUP-TF1 may be associated with improved patient survival, the aim of her research, for which she has applied for a CURE grant, is to determine how the biomarker affects retonic acid response, a vital component of therapy. She also hopes to demonstrate that the expression of COUP-TF1 in neuroblastoma tumors does correspond to improved patient survival.

 

Dr. Goldsmith joined Children’s Healthcare of Atlanta in the fall of 2009, and her current experiments build on earlier research she completed at Children’s Hospital of Philadelphia. Regarding her transition to Atlanta, she says, “One thing I really like about being here is the drive to translate from bench to bedside,” Goldsmith says. “I think that is such a huge focus and here they are really trying to make it a reality.”

 

Throughout her career, Dr. Goldsmith has received many honors for her continuing contributions to pediatric research and care. Her most recent awards include: the 2008 American Cancer Society Mentored Research Scholars Award; the 2006 Hope Street Kids Foundation Award; the 2005 American Society of Clinical Oncology (ASCO) Cancer Foundation Young Investigator Award; and the 2004 Caitlin Robb Foundation Award.