As physicians and scientists at Texas Children’s Cancer Center are working to find better treatments that will lead to cures for childhood cancer, they are increasingly turning to large-scale genetic (“genomic”) approaches to understand the causes of these diseases and develop novel therapies to treat them.
This type of research was not possible as recently as 10 years ago but today it extends across all types of childhood cancer, including brain cancer, leukemia, osteosarcoma, neuroblastoma and even rarer pediatric cancers.
”The application of genomic technologies to the study of childhood cancers is likely to be transformational in its impact,” Dr. David Poplack, leader of the Dan L Duncan Cancer Center’s Pediatric Program and director of Texas Children’s Cancer Center.
One example is the collaborative osteosarcoma research project led by Dr. Lisa Wang, associate professor of pediatric oncology at Baylor College of Medicine. She oversees a $6 million grant from the Cancer Prevention and Research Institute of Texas for the project that brings together researchers from multiple institutions, including The University of Texas MD Anderson Cancer Center and Texas A&M University, who are experts in pediatric oncology, molecular cancer biology, genomics, proteomics, immunotherapy and cancer animal models to study and treat osteosarcoma, the most common bone cancer in children.
“The outcomes for patients with metastatic osteosarcoma have remained stagnant for nearly three decades at about 25 percent survival,” Wang said, “so there is an urgent need for more effective and less toxic therapies.”
The three-part project employs novel mouse models to investigate critical genetic events important for metastasis (the spread of cancer to other organs in the body); uses high-throughput, multi-platform genomic and proteomic approaches to identify novel biomarkers of metastatic potential; and focuses on immunotherapy—harnessing the body’s own immune cells—to treat osteosarcoma.
Investigators have completed a “first-in-human” Phase I/II clinical trial to evaluate the safety and antitumor effects of escalating doses of the patient’s own T cells engineered to recognize the HER2 protein, which is expressed in about 60 percent of osteosarcoma tumors. Through multi-platform profiling approaches using novel genetically engineered mouse models as well as patient tumor samples, they also have identified several gene pathways and plasma proteins that are being validated as biomarkers of disease and potential targets of therapy in metastatic osteosarcoma.
Genomic Sequencing and Pediatric Cancers
“It’s important to note that this is truly a collaborative study that involves multiple departments and disciplines. This type of project can only be done at a place like Baylor and Texas Children’s Cancer Center."–Dr. Sharon Plon
Researchers also are working to understand how to apply these newly-developed genomic sequencing methods to the clinical setting to improve the care for children with cancer. A project underway at in the DLDCC Pediatric Program, located at Texas Children’s Cancer Center, is at the forefront of this effort. Led by BCM investigators Drs. Sharon Plon, a cancer geneticist, and Will Parsons, a pediatric oncologist, the Baylor Advancing Sequencing in Childhood Cancer Care, or BASIC3, project was funded through a $6.6 million grant from the National Human Genome Research Institute and the National Cancer Institute.
The overall goal of this project is to integrate blood and tumor whole exome sequencing information obtained at the time of diagnosis into the clinical care of childhood cancer patients with high-risk solid tumors and brain tumors. It includes three key components:
Development of the infrastructure and expertise to perform clinical genomic testing and evaluation of the clinical utility of that approach for newly-diagnosed pediatric solid tumor patients, in regards to both cancer treatment and prevention
Improvement of methods for the sequencing, analysis, interpretation and reporting of genomic data for childhood cancer patients
Exploration of the ethical and social issues related to genomic testing, including the preferences of both families and oncologists for the reporting of these complex results and improving their communication between families and oncologists.
Researchers are more than halfway to the targeted goal of 280 study subjects and key milestones and accomplishments have already been achieved, including:
Successful establishment of a pipeline for clinical sequencing of blood and tumor specimens from pediatric oncology patents.
Creation of efficient and family-sensitive processes for obtaining informed consent for genomic studies and for returning results to families by a genetic counselor and the patient’s primary oncologist.
Identification of diagnostic and potentially actionable results in nearly 40 percent of pediatric solid tumor patients, including both cancer and non-cancer related findings.
“The BASIC3 study is the first study of the process and utility of performing clinical exome sequencing for pediatric oncology patients,” said Parsons. “These results are crucial as we now plan clinical trials of molecularly-targeted therapies and develop ‘personalized’ treatment approaches for our patients.”
“It’s important to note that this is truly a collaborative study that involves multiple departments and disciplines, including Dr. Sue Hilsenbeck of the Dan L Duncan Cancer Center biostatistics core. This type of project can only be done at a place like Baylor and Texas Children’s Cancer Center,” said Plon, who is also a professor of molecular and human genetics at Baylor. •