The long-term goal of our work is to improve outcomes for children with cancer. Several decades’ worth of cooperative group studies have greatly increased the survival of children diagnosed with cancer, through clinical trials to refine the use of multiagent chemotherapy. Despite this progress, significant challenges remain. About 25 percent of children with cancer will succumb to their disease. Even for those who are cured, troubling late effects of chemotherapy can cause lifelong disability and shortened life expectancy. For these reasons, new approaches that are more effective and less toxic are urgently needed.

By understanding the pathogenesis of childhood cancers at a molecular level, we hope to gain critical insight that will identify robust clinical biomarkers (allowing therapy to be tailored appropriately for risk) and identify targets for novel, more effective therapies. Our research focuses on several types of solid tumors in children, integrating several complementary approaches including zebrafish genetic models, in vitro work and high-resolution genomic studies of these cancers.

Zebrafish Models

We use the zebrafish system to take a genetic approach to understanding these tumors. Zebrafish have anatomy, physiology and cancer susceptibility very similar to humans, making them an excellent cancer model. The system further offers unique advantages for developmental biology studies and forward genetic screens.

The goal here is to identify mutations in the zebrafish that cause specific types of cancers, and thereby gain insight into what mechanisms cause the same types of cancers in children.

For example, we recently identified a novel mutation that disrupts the Bone Morphogenetic Protein (BMP) signaling pathway and causes germ cell tumors in zebrafish. In collaboration with the Children’s Oncology Group (COG), we have found that BMP signaling is also aberrantly regulated in human germ cell tumors.

In other work, the lab has made a transgenic model of Ewing’s Sarcoma in zebrafish, with the goal of discovering modifier genes and screening small molecule libraries to identify candidates for more effective, targeted therapy of human Ewing’s Sarcoma.

Genomics of Childhood Cancers

We are using next-generation sequencing approaches to understand the molecular basis of childhood cancers, including malignant germ cell tumors and Wilms tumor, the most common form of kidney cancer in children. Using these techniques lets us examine tumors at the level of specific DNA mutations.

Discovering the nature of these mutations allows us to understand in a much more sophisticated way what it is that drives the tumor cells to grow out of control. Critically, this knowledge should make it possible to design new treatments for childhood cancer that are specifically targeted to the genetic lesions in that type of cancer.

The goal is to make treatments that are more effective than our current treatments, while at the same time exposing children to fewer toxic side effects of treatment. The zebrafish also plays a key role here, because many of the mutations that we and others uncover have not been previously studied, and modeling the effect of these mutations in fish can be extremely helpful in understanding how the mutations cause cancer, and in developing new treatment approaches.