TARGETing the Clinic: Translating Discoveries for Pediatric Cancer

November 1, 2017, by Jaime M. Guidry Auvil, Ph.D.

September was Childhood Cancer Awareness Month, which inspired us to reflect back on the multiple successes that OCG’s TARGET (Therapeutically Applicable Research to Generate Effective Treatments) initiative has made towards the advancement of pediatric cancer research and treatment.

Cancer is leading the cause of death by disease for children over the age of one year,¹ and young adults, in the United States. Each year nearly 15,000 children are diagnosed with some form of cancer, resulting in an approximate 1,200 deaths.² While significant strides have been made towards improving the clinical outcomes for pediatric cancer patients, several deficiencies remain that require focused attention. These include:

• About 20% of pediatric cancer patients do not respond to standard therapy and ultimately succumb to their diseases. 
• Current treatments are toxic and particularly harsh on growing children. Survivors are often impacted by onset of secondary cancers, developmental delays, physical and emotional health issues, and infertility.
• Current treatment protocols are mostly derived from therapeutic regimens that were formulated for adult cancers. Previous studies revealed that childhood cancers are often genetically distinct from their adult counterparts, suggesting the need for alternate treatment approaches.

The TARGET initiative set out to improve patient outcomes through a collaborative team science approach. Individual disease project teams are composed of clinicians, genomics experts, laboratory and data scientists; many of whom are members of the Children’s Oncology Group (COG). COG is a cooperative group devoted exclusively to pediatric clinical trials, provided the TARGET project teams access to high-quality tissue samples with clinical annotation, as well as the potential for rapid translation of molecular findings into novel therapies. TARGET researchers have worked together within and across disease projects to successfully generate, analyze, integrate, and interpret high quality, comprehensive genomics, transcriptome and epigenomics data. TARGET project teams have made significant discoveries and translating some that are clinically-actionable (for personalized and/or targeted therapies) for patients. Examples to date are highlighted below.

Key TARGET Discoveries in Childhood Cancers

Cancer Type	Genomic Discovery	Clinical Translation
Ph-like ALL (BCR-ABL1-like ALL)	Gene expression profiles similar to Ph+ ALL Poor outcome for patients Frequency increases with age (prevalent in young adults) Kinase activating lesions in ~90% of cases High frequency of rearrangements & fusions that are highly responsive to TK inhibitors (imatinib, dasatinib, ruxolitinib, crizotinib) in vitro & in humans (Roberts et al., NEJM, 2014; Mullighan et al., NEJM, 2009; & Others)	COG ADVL1011 / COG AALL1521 Phase I & Phase II trials of Janus kinase (JAK) inhibitor Ruxolitinib in patients with known CRLF2 or JAK mutations  COG AALL131 Phase III trial to study efficacy combination chemo for young patients with HR B-ALL; amended to include Dasantanib in patients with Ph-like ALL & ABL-class fusions
High Risk Neuroblastoma	Confirmed GWAS findings of significant oncogenic & rare pathogenic germline variants enriched in ALK Genetic predisposition to neuroblastoma is mediated by a LMO1 super-enhancer polymorphism Activating mutations RAS-MAPK pathway in relapsed NBL tumors (78% cases studied) (Pugh et al., Nature Genetics, 2013; Eleveld et al., Nature Genetics, 2015; & Oldrige et al., Nature, 2015)	COG ADVL0912 Phase I/II trial ALK inhibitor Crizotinib (ALK mut/amp); determined safe at recommended doses (Mosse’ et al., Lancet Oncol, 2013)
Acute Myeloid Leukemia	Differences in frequency of genes expressed between adult & pediatric AML. TP53 and IDH1/2 mutations are rare, and DNMT3A mutations are absent in childhood disease miRNA signature predictive of outcome in pediatric AML Distinct molecular subtype of pediatric AML is defined by CSFR mutations (most with CEBPA or CBF translocations); some specific mutations are shared with adult CNL  90% of the variants (VAF >0.4) found at diagnosis persisted to relapse in pediatric AML (Maxson et al., Blood, 2016 & Farrar et al., Cancer Res, 2016)	TARGET AML project PIs received a grant to develop immunotherapies against targets found in TARGET analyses, with potential for future clinical trials
High Risk Wilms Tumor	Comprehensive analyses suggests Wilms Tumor (WT) results from key genetic changes in a limited number of renal developmental pathways. Relapsed Favorable Histology WT Recurrent mutations in key miRNA processing genes (DGCR8, DROSHA) & SIX1/2 homeobox genes a higher rate relapse/death Activating MLLT1 mutation early in renal development a WT Diffuse Anaplastic WT Confirm TP53 defining mutation develop anaplasia (>95%)​ (Gadd et al.,Nature Genetics, 2017; Perlman et al., Nature Comms, 2015; Waltz et al., Cancer Cell, 2015; & Ooms et al., Clinical Cancer Research, 2016.)	TARGET findings confirm some other key discoveries in WT, which are leading to a reduction in toxic treatment for patients who are not likely to relapse; identification of those through stratification of patients by 1q gain & loss of 16q,1p (planned standard protocol for WT treatment)

TARGET project teams continue to address challenges of pediatric cancers through mining and analyzing the data. They are completing trans–TARGET analyses (together with informatics experts at St. Jude’s Children’s Research Hospital and Children’s Hospital of Philadelphia) to uncover somatic and germline alterations both within and across the various childhood cancers studied. Manuscripts are being finalized, and all TARGET datasets (open and controlled access tiers) are available for the research community to mine through the TARGET Data Matrix. Sequence data can be accessed from NCBI’s Sequence Read Archive (SRA), as well as NCI’s Genomic Data Commons (GDC) with approval through NCBI’s database of Genotypes and Phenotypes (dbGaP). The successes of TARGET will continue to expand the biologic knowledge of and potential therapeutic intervention for pediatric disease when the larger community comes together to collaborate and work across all available resources.

References:

1. https://www.cancer.gov/types/childhood-cancers

2. https://www.cancer.gov/about-cancer/understanding/statistics