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Principal Investigator: Dana Ashley Hill
Organization: CHILDREN'S RESEARCH INSTITUTE
Fiscal Year: 2019
Award: $395,349
Funding agency: National Cancer Institute
DESCRIPTION (provided by applicant): Studies of inherited cancer syndromes have provided unique opportunities to uncover and explain important cellular pathways with broad relevance to both sporadic cancers and human development. This proposal studies the cancer predisposition syndrome originally described as a familial form of pleuropulmonary blastoma (PPB). PPB is an aggressive lung cancer that affects young children. Children with PPB and/or their family members are at increased risk for a number of conditions, including Wilms tumor, rhabdomyosarcoma, brain tumors, ovarian tumors and nodular hyperplasia of the thyroid gland. In 2009, we mapped a PPB locus and identified germline, loss of function mutations in one copy of DICER1 as a risk for developing PPB. DICER1 encodes a protein that performs the final critical step in maturation of microRNAs (miRNAs). miRNAs are an important form of gene regulation. Sequencing studies have revealed a unique pattern of mutations in both copies of the DICER1 gene in tumors. Generally, one copy of DICER1 has complete loss of function, while the other copy has a mutation that prohibits DICER1 from cleaving an important subclass of miRNAs. Tumors are deficient in miRNAs that serve as the "brakes" for the genes responsible for rapid growth of the embryo during gestation, so-called "oncofetal" genes. In Aim 1 of this proposal we will determine the critical oncogenes needed for PPB cell survival through which we hope to also gain insight into the normal suppression of tumorigenesis during human development. In Aim 2 we propose to replace deficient miRNAs (let-7 and others) to restore natural regulation of this developmental program and push tumor cells into apoptosis or permanent maturation. Specific sub-aims will be development of the first mouse xenograft models of PPB and ovarian Sertoli-Leydig cell tumors, which will be indispensable for preclinical testing, and application of a novel, third generation technology for therapeutic gene silencing known as U1 Adaptors. Aim 3 will focus on important, unresolved questions regarding the genetic pathogenesis and risk for malignancy in the two most common conditions in DICER1 syndrome mutation carriers, benign thyroid nodules and lung cysts. Conceptually, PPB represents a naturally-occurring, developmental model of embryonal organ-based neoplasia. We hope that understanding the natural controls on this oncofetal gene program can be leveraged into novel therapeutic approaches for PPB and other childhood neoplasms.
Terms: <0-11 years old><Address><Affect><After Care><After-Treatment><Aftercare><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Apoptosis><Apoptosis Pathway><BABL><BABL Gene><Benign><Biogenesis><Brain Neoplasia><Brain Neoplasms><Brain Tumors><Cancer Family><Cancer Genes><Cancer-Promoting Gene><Cancers><Cell Body><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Proliferation><Cell Survival><Cell Viability><CellLine><Cells><Cellular Expansion><Cellular Growth><Cellular Proliferation><Child><Child Youth><Childhood Cancers><Childhood Neoplasm><Childhood Tumor><Children (0-21)><Cleaved cell><Clinical><Cultured Neoplastic Cells><Cultured Tumor Cells><Cyst><DICER Gene><DICER1><DICER1 gene><Defect><Development><Early Diagnosis><Embryo><Embryonic><Enzyme Gene><Enzymes><Expression Profiling><Family><Family member><Fetal Lung><Gene Action Regulation><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Expression Regulation><Gene Inactivation><Gene Regulation><Gene Regulation Process><Gene Silencing><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genotype><Gestation><Goals><HERNA><HMG I-C Protein><HMGA2><HMGA2 Protein><HMGA2 gene><HMGI-C><HMGI-C Protein><HMGIC><HMGIC Gene><Helicase with RNase Motif><Helicase-MOI><Hereditary><High Mobility Group AT-Hook 2><High Mobility Group AT-Hook 2 Gene><High Mobility Group Protein HMGIC Breakpoint Associated with Benign Lipoma><High Mobility Group Protein HMGIC Breakpoint Associated with Benign Lipoma Gene><High Mobility Group Protein Isoform I-C><High Mobility Group Protein Isoform I-C Gene><High-Mobility Group (Nonhistone Chromosomal) Protein Isoform I-C><High-Mobility Group (Nonhistone Chromosomal) Protein Isoform I-C Gene><High-Mobility Group Protein HMGI-C><High-Mobility Group Protein HMGI-C Gene><Human Development><Hyperplasia><Hyperplastic><In Vitro><Inherited><Interstitial Cell Neoplasm><Interstitial Cell Tumor><K12H4.8-Like><KIAA0928><Kinetics><LIPO Gene><Lead><Leydig Cell Neoplasm><Leydig Cell Tumor><Link><Lung><Lung Respiratory System><Malignant><Malignant - descriptor><Malignant Cell><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Neoplasms><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant Tumor><Malignant Tumor of the Lung><Malignant childhood cancer><Malignant neoplasm of lung><Maps><Measures><Mice><Mice Mammals><Micro RNA><MicroRNAs><Missense Mutation><Modeling><Molecular><Murine><Mus><Mutation><NT mimic 2><Neoplasms><Nephroblastoma><Oligo><Oligonucleotides><Oncogenes><Oncogenesis><Organ><Origin of Life><Ovarian><Ovarian Tumor><Ovary Neoplasms><Ovary Tumor><Pathogenesis><Pathway interactions><Patients><Pattern><Pb element><Pediatric Neoplasm><Pediatric Tumor><Phase><Pilot Projects><Pleuropulmonary Blastoma><Preclinical Testing><Predisposition><Pregnancy><Premalignant Neoplasm><Progenitor Cells><Programmed Cell Death><Proteins><Pulmonary Cancer><Pulmonary malignant Neoplasm><Regulation><Regulator Genes><Regulatory Pathway><Renal Wilms' Tumor><Rhabdomyosarcoma><Risk><Role><Stem cells><Strains Cell Lines><Susceptibility><Syndrome><Technology><Therapeutic Agents><Therapeutic Effect><Thyroid><Thyroid Gland><Thyroid Gland Nodule><Thyroid Head and Neck><Thyroid Nodule><Transcript Expression Analyses><Transcript Expression Analysis><Transcriptional Regulatory Elements><Transforming Genes><Tumor Cell><Wilm's Tumor><Wilms Tumor><Wilms' Tumor of the Kidney><Work><Xenograft Model><base><cancer cell><cancer in a child><cancer in children><cell growth><child with cancer><childhood malignancy><children><children with cancer><childrens'><cleaved><combinatorial><cultured cell line><design><designing><developmental><early childhood><early detection><gene expression analysis><gene expression assay><gene therapeutics><gene-based therapeutics><genes therapeutic><genes therapeutics><genome mutation><heavy metal Pb><heavy metal lead><insight><lipid nanoparticle><loss of function><loss of function mutation><lung cancer><lung development><mRNA Expression><malignancy><miRNA><miRNAs><mimic 2><model of animal><model organism><mutant><mutation carrier><mutation status><mutational status><neoplasia><neoplasm/cancer><neoplastic cell><neoplastic growth><neurotensin mimic 2><new approaches><new drug treatments><new drugs><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutics><novel therapy><novel therapy approach><oligos><oncofetal antigen><oncofetal proteins><organ development><organ growth><ovarian neoplasm><overexpress><overexpression><pathway><pediatric cancer><pediatric malignancy><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><pilot study><post treatment><pre-clinical testing><programs><public health relevance><pulmonary><rapid growth><reconstitute><reconstitution><regulatory gene><response><senescence><senescent><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic gene><trans acting element><transcriptional profiling><transcriptional silencing><tumor><tumorigenesis><tumors in children><tumors in the brain><youngster>