DICER-Dx: The First Liquid Biopsy for Early Detection and Monitoring of DICER1 Syndrome Pediatric Cancers

PROJECT SUMMARY ABSTRACT Pleuropulmonary blastomaPPBis the most common lung cancer of childhoodand usually the earliest indication of DICERsyndromea genetic predisposition to early onset embryonal tumors of multiple organ sitesThe syndrome is defined by germline mutations in the DICERgeneOMIMIn addition to PPBthe spectrum of syndromic neoplasias includes ovarian Sertoli Leydig cell tumorcystic nephroma and renal sarcoma or Wilms tumorembryonal rhabdomyosarcomanodular hyperplasia and carcinoma of the thyroid glandnasal chondromesenchymal hamartomapituitary blastoma and pineoblastomaEarly detection is imperative for survival in children with PPBWhen discovered in its earliestcystic stagecalled Type I PPBof children diagnosed and treated for Type I PPB surviveThe outcomes for children with cystic and solidType IIand purely solidType IIIPPB are significantly worse despite surgery and intensive multidrug chemotherapyAbout half of children with Type III PPB survive long termThere are no effective treatments for refractory or recurrent diseaseLate diagnosis and the resistance to therapy are the two major barriers to improving survivals of children with PPBGenetic pathogenesis in DICERsyndrome is uniqueand it suggests a solution to the detection problems that hinder clinical managementFrom sequencing studies in overcases of PPB and other DICERsyndrome cancerswe know that virtually all carry a second DICERmutationacquired somatically during early developmentWe propose to develop DICER Dxa panel of droplet digital PCRddPCRassays for the detection and quantification of DICERhotspot mutationswhich are specificallyand invariablyassociated with DICERsyndrome cancersDICER Dx will be the first noninvasive biomarker assay for DICERsyndrome cancersIt has the potential to transform standards of care for PPB and DICERsyndrome byImproving the specificity and sensitivity of surveillance for tumor emergence in children at riskwhile reducing or eliminating the need for CT scans and the attendant risks from radiation exposure and sedationClarifying the differential diagnosis of Type I PPB vsbenign lung cysts discovered in imaging studiesGuiding treatment decisions for children with PPB or other DICERsyndrome tumorse gwhether or not adjuvant chemotherapy is needed after surgical removal of Type I PPBMonitoring for recurrence following chemotherapyandEvaluating tumor response to therapyDICER Dx may be useful not only in monitoring response to therapy in children with tumorsbut also in preclinical mouse modelsDICERDx sample collection and testing will be an essential component of treatment and biology studies for the International PPB Registry Project Narrative An estimatedinindividuals carry germline mutations in DICERwhich is associated with predisposition to a group of childhood cancersIn this Phase I SBIRResourcePath plans to develop a diagnostic blood test that can detect the earliest development of cancer or recurrence in children with cancers associated with DICERmutationsDetecting tumors earlier when they are most responsive to therapy will improve survival for pleuropulmonary blastoma and related tumors such as rhabdomyosarcomaSertoli Leydig cell tumorsand Wilms tumor