Protocol Develops New Models of Recurrent Pediatric Solid Tumors

Kristin Jenkins

August 31, 2017

A new collection of data on rare solid pediatric tumors has been developed by researchers at  St Jude Children's Research Hospital, New York City, and has been made available at no charge to the global scientific community.

The Childhood Solid Tumor Network includes data from orthotopic patient-derived xenografts (O-PDXs), where human tumors are grown in the same organ in mice; the standard approach is to grow patient tumors in the flanks of mice.

The researchers hope that this work, described in a report published online August 30 in N ature, will eventually lead to improved survival rates.

"Survival rates for children with recurrent solid tumors have not improved significantly in more than 20 years and remain below 30%," said corresponding author, Michael Dyer, PhD, chair of St Jude's Department of Developmental Neurobiology and a Howard Hughes Medical Institute investigator.

"This research will change that by promoting scientific collaboration to leverage the efforts of researchers worldwide to advance understanding and ultimately treatment of pediatric solid tumors," he said in a statement.

The team used tumor specimens from 168 pediatric patients to develop 67 O-PDXs grown in the same organs in mice, covering 12 types of cancer.

These xenografts have also been used to generate more than 500,000 data points on drug sensitivity that can help identify the most promising compounds to move into clinical trials, the researchers explain.  

To date, O-PDXs have been used to identify rhabdomyosarcoma as the high-risk pediatric solid tumor most likely to respond to the experimental drug AZD1775 (AstraZeneca) in combination with irinotecan (Camptosa r; Pfizer) and vincristine (Oncovin). The investigational drug, which acts as a selective inhibitor of Wee1 kinase, is being considered for inclusion in an ongoing national clinical trial looking at the combination chemotherapy in pediatric patients with select high-risk solid tumors, the researchers say.

"This study shows that orthotopic patient-derived xenografts can serve as a bridge connecting basic and translational research to improve outcomes for patients," Dr Dyer said in a statement. "It serves as the gold standard for development, characterization and use of patient-derived tumors."

A comprehensive analysis shows that many O-PDXs retain their molecular identity even after being grown in successive generations of mice. Importantly, orthotropic xenografts representing neuroblastoma, osteosarcoma, Wilms tumor, retinoblastoma, rhabdomyosarcoma, and other less common tumors provide more accurate models for tracking tumor development and drug sensitivity than the standard approach of growing patient tumors in the flanks of mice, the researchers point out.

"Pediatric solid tumors represent a wide spectrum of cancers that affect kids of all ages," commented lead investigator, Elizabeth Stewart, from the oncology and developmental neurobiology departments at St Jude's. "There has not been significant improvement in the survival rates for many of these cancers over the last 20 years, particularly those with recurrent and metastatic disease," she told Medscape Medical News.

The team is hoping that other promising compounds can be identified and tested by engaging scientific researchers through their Childhood Solid Tumor Network (CSTN). In addition to the 5 osteosarcoma cell lines widely used to study osteosarcoma, for example, 20 additional patient tumor samples are now available. Similarly, research resources for retinoblastoma have increased from 2 cell lines to 18 tumor samples.

"The CSTN has significantly expanded scientific resources for pediatric solid tumor research," said Dr Stewart, calling the network "the world's largest collection of pediatric solid tumor samples." It includes many rare tumors as well as tumors collected at disease recurrence, which are most difficult to treat, she pointed out.

Plans are also underway to develop additional O-PDXs and to include induced pluripotent stem cells taken from children genetically predisposed to cancer. "Studying the mechanisms behind which these cells transform into cancer will advance our understanding and ultimately treatment of pediatric solid tumors," she said.

The network provides samples free of charge, and accessing the resources and drug sensitivity data requires no commitment to collaborate with St Jude scientists, she emphasized.

Funding for this research was received from the National Institutes of Health, Cancer Center Support, American Lebanese Syrian Associated Charities, Alex's Lemonade Stand Foundation for Childhood Cancer, the Tully Family Foundation, the Peterson Foundation, St Baldrick's Foundation and the Invictus Fund, the National Pediatric Cancer Foundation, and the Howard Hughes Medical Institute. The authors have disclosed no relevant financial relationships.

Nature. Published online August 30, 2017. Full text

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