Pleuropulmonary blastoma (PPB) is the most common lung cancer of childhood, now known to be related to pathogenic variation in DICER1, a critical regulator of embryogenesis. Nearly all clinically significant PPB is diagnosed in children under 7 years of age. Type I PPB is a purely cystic tumor with a layer of primitive malignant cells. Type I PPB may progress to Type II PPB, a mixed cystic and solid tumor, or Type III PPB, a highly aggressive, purely solid sarcoma. Children with Type I PPB are treated with surgery with or without chemotherapy; however it is not clear which children require chemotherapy and which children can be safely observed. Children with Type II or III PPB face an overall survival of only 74 and 53% respectively. In Types I, II and III PPB, there is a need for risk stratification so that children with residual or progressive disease can receive more intensive tumor-directed treatment and children with a favorable prognosis can be spared unnecessary side effects. Since 1988, the International PPB Registry, based at Children?s Minnesota, has been enrolling children with PPB in an effort to improve outcomes for this rare tumor. Our industrial partner, ResourcePath, has developed DICER-Dx, a blood-based assay to detect DICER1hotspot circulating tumor DNA (ctDNA). We hypothesize that the unique molecular pathogenesis of DICER1-related tumors can be exploited to facilitate tumor monitoring in PPB. This project focuses on 1) the clinical validation of novel liquid biopsy assays for sensitive detection and quantification of tumor burden in Types I, II and III PPB and 2) delivery of current and future DICER1-related advances to children globally, leveraging our emerging partnership with Beijing Children?s Hospital to increase accrual and accelerating successful completion of the proposed work. Relevance: These assays will apply to children and adults with DICER1-related cancers and improve upon existing tumor monitoring while minimizing the risks of diagnostic radiation and sedation. DICER-Dx provides a new way to measure DICER1-related cancer burden and response to therapy and therefore represents a pioneering application of liquid biopsy technology in childhood cancer. These assays may be useful not only in clinical practice, but also as companion diagnostics in preclinical drug development and clinical trials and will be an essential component of future translational studies for the International PPB/DICER1 Registry. Additionally, validation of these biomarkers is the next critical step in our efforts to develop ctDNA-based biomarkers for use in healthy children and young adults with DICER1 pathogenic variation at elevated risk of DICER1-related cancers.

Public Health Relevance

Clinical validation and translation of blood-based biomarkers is the next necessary step in our efforts to cure PPB and other DICER1-related cancers. This global partnership focuses on the clinical validation of novel circulating tumor DNA-based 'liquid biopsy' assays for quantification of tumor burden and detection of treatment response in DICER1-related cancers. Development of novel biomarkers will improve outcomes for children and adults with DICER1-related cancers through early diagnosis, risk stratification and intervention and development of novel therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Mckee, Tawnya C
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Children's Hospitals and Clinics
United States
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