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Principal Investigator: Jatinder K. Lamba
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $636,388
Funding agency: National Cancer Institute
ABSTRACT: Acute myeloid leukemia (AML) is a rare, devastating, and understudied malignancy with ~20,00 new cases
and around 61,000 cases in US. Though intensive chemotherapy primarily consisting of ara C (also known as cytarabine),
daunorubicin, and etopside have been used to treat AML for over 4 decades, only 65%, 40%, and 10% of pediatric (age
<21), adult (age 21-65), and elderly (age > 65) patients survive 5 years after diagnosis, respectively. Application co-PIs,
Drs. Lamba (pharmacology) and Pounds (biostatistician specializing in cancer genomics) have successfully collaborated
for over a decade to develop methods and discover molecular prognostic factors for AML. We and other investigators from
Children’s Oncology group have recently characterized the genome, methylome, and transcriptome of pediatric AML and
associated each of these with prognosis in pediatric AML. Dr. Pounds developed the innovative integrative analysis
procedure, canonical correlation with projection onto the most interesting statistical evidence (CC-PROMISE), that
dramatically increases statistical power for meaningful biological discovery in a rare-disease small sample size setting;
using CC-PROMISE, we discovered that reduced methylation and increased expression of the DNMT3B associates with
greater genome-wide methylation burden and worse prognosis; translating the DNMT3B discovery into evaluation of
demethylating agents in the ongoing AML16 clinical trial (NCT03164057). These genomic, epigenomic, and transcriptomic
features, along with microenvironmental and other factors, must impact the proteome and metabolome of AML in clinically
relevant ways which unfortunately are not well understood. There has been essentially no study focused on comprehensive
evaluation of the proteome and metabolome of pediatric AML in a reasonable cohort of uniformly treated patients. Noting
the marked genomic, transcriptomic, methylomic, and prognostic differences between pediatric and adult AML, it is not
plausible to extrapolate finding from adult AML patients to pediatric. Thus an integrated systems-level understanding of
the molecular disease biology is needed to develop effective strategies and improve the prognosis of pediatric AML. As
pioneers in the collection and integrated analysis of the pediatric AML genome, methylome, and transcriptome,
application co-PIs Drs. Lamba and Pounds are uniquely positioned to characterize the proteome and metabolome
of pediatric AML and integrate them with our large repository of previously collected molecular, treatment, and
outcome data for a series of multi-center clinical trials. Thus, in this application we propose to characterize global
metabolome (aim 1) and proteome (aim 2) the leukemic cell obtained at diagnosis for risk stratification and prognosis by
evaluating impact on outcome in three St Jude led multi-institute clinical trials (AML02, AML08 and AML16, total patients
n=400). In aim 3, we plan to develop a comprehensive integrated view of the genome, methylome, transcriptome,
proteome, metabolome, and clinical prognosis of pediatric AML using novel methods. These innovative and
exceptionally rigorous studies will be the first comprehensive evaluation of the pediatric AML metabolome and proteome
and develop an innovative integrated analysis method to perform the first integrated analysis of five forms of omic data with
multiple clinical endpoints to obtain the most complete understanding of pediatric AML systems biology to date.
Terms: <1.beta.-D-Arabinofuranosylcytosine><21 year old><21 years of age><21+ years old><5 AZC><5-AC><5-Aza-cytidine><5-Azacytidine><5-Azadeoxycytidine><5-deoxyazacytidine><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AML - Acute Myeloid Leukemia><ARA-cell><AZC><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Adult><Adult AGL><Adult AML><Adult ANLL><Adult Acute Granulocytic Leukemia><Adult Acute Myeloblastic Leukemia><Adult Acute Myelocytic Leukemia><Adult Acute Myelogenous Leukemia><Adult Acute Myeloid Leukemia><Adult Acute Non-Lymphoblastic Leukemia><Adult Acute Non-Lymphocytic Leukemia><Adult Acute NonLymphoblastic Leukemia><Adult Acute NonLymphocytic Leukemia><Adult Human><Aged 65 and Over><Alexan><Ara-C><Arabine><Arabinofuranosylcytosine><Arabinosylcytosine><Aracytidine><Aracytin><Aracytine><Azacitidine><Azacytidine><Biological><Biology><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancers><Cas nuclease technology><Cell Line><CellLine><Cerubidin><Characteristics><Childhood><Childhood AML><Childhood Acute Granulocytic Leukemia><Childhood Acute Myeloblastic Leukemia><Childhood Acute Myelocytic Leukemia><Childhood Acute Myelogeneous Leukemia><Childhood Acute Myelogenous Leukemia><Childhood Acute Myeloid Leukemia><Childhood Leukemia><Children's Oncology Group><Classification><Clinical><Clinical Data><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Collaborations><Collection><Creatinine><Custom><Cytarabine><Cytarabinum><Cytarbel><Cytosar><Cytosar-U><CytosarU><Cytosine Arabinoside><Cytosine-.beta.-arabinoside><D-Glucose><DNA Alteration><DNA Methyltransferase 3B><DNA Sequence Alteration><DNA mutation><DNMT3B gene><DNMT3b><Data><Dauno-Rubidomycine><Daunoblastina><Daunoblastine><Daunomycin><Daunorrubicina><Daunorubicin><Decitabine><Deoxyazacytidine><Development><Dextrose><Dezocitidine><Diagnosis><Diagnostic><Drugs><EPEG><Elderly><Enrollment><Environment><Eposide><Erpalfa><Etoposide><Evaluation><Exposure to><Florida><General Prognostic Factor><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Genome><Genomics><Glucose><Guidelines><Investigators><Kinases><Knock-out><Knockout><Lastet><Leukaemomycin C><Leukemic Cell><Malignant Neoplasms><Malignant Tumor><Medication><Methods><Methylation><Molecular><Molecular Disease><Multi-Institutional Clinical Trial><Multi-center clinical trial><Multi-site clinical trial><Multicenter clinical trial><Multiomic Data><Multisite clinical trial><Mutation><Ondena><Orphan Disease><Outcome><Pathway interactions><Patient risk><Patients><Pediatric AML><Pediatric Acute Myeloblastic Leukemia><Pediatric Acute Myelocytic Leukemia><Pediatric Acute Myelogeneous Leukemia><Pediatric Acute Myelogenous Leukemia><Pediatric Acute Myeloid Leukemia><Pediatric Leukemia><Pediatric Oncology Group><Pediatric cohort><Pharmaceutical Preparations><Pharmacology><Phosphotransferase Gene><Phosphotransferases><Position><Positioning Attribute><Procedures><Prognosis><Prognostic Factor><Prognostic Marker><Prognostic/Survival Factor><Proteins><Proteome><Proteomics><Qualifying><Randomized><Rare Diseases><Rare Disorder><Recommendation><Recurrence><Recurrent><Reporting><Research><Research Personnel><Researchers><Risk><Rubidomycin><Rubilem><Rubomycin><Rubomycin C><Saint Jude><Saint Jude Children's Cancer Center><Saint Jude Children's Research Hospital><Sample Size><Sampling><Sequence Alteration><Series><St. Jude><St. Jude Children's Cancer Center><St. Jude Children's Research Hospital><St. Jude Children's Research Hospital Comprehensive Cancer Center><St.Jude Children's Cancer Center><St.Jude Children's Research Hospital><St.Jude Children's Research Hospital Comprehensive Cancer Center><Strains Cell Lines><System><Systematics><Systems Biology><Tarabine PFS><Therapeutic Intervention><Translating><Translational Research><Translational Science><Transphosphorylases><Transplantation><Udicil><Universities><Vepesid><Work><above age 65><acute granulocytic leukemia><acute granulocytic leukemia cell><acute myeloblastic leukemia cell><acute myelocytic leukemia cell><acute myelogenous leukemia cell><acute myeloid leukemia><acute myeloid leukemia cell><acute nonlymphocytic leukemia cell><adulthood><advanced age><after age 65><age 21><age 21 years><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged ≥65><amino acid metabolism><biologic><cancer genomics><cerubidine><chemotherapy><children with AML><children with acute myeloid leukemia><children with leukemia><clinical prognosis><clinical relevance><clinical translation><clinically relevant><clinically translatable><cohort><cultured cell line><customs><demethylation><depository><developmental><drug/agent><effective therapy><effective treatment><enroll><epigenomics><genome mutation><genome wide methylation><genomewide methylation><genomic alteration><geriatric><global gene expression><global methylation><global transcription profile><hDNA methyltransferase 3b><human old age (65+)><improved><innovate><innovation><innovative><intervention therapy><ladakamycin><leukemia in children><malignancy><meeting><meetings><metabolism measurement><metabolome><metabolomics><metabonome><metabonomics><methylome><methylomics><multiple omic data><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><old age><oncogenomics><orphan disorder><over 65 years><pathway><pediatric><pharmacologic><prognostic><prognostic biomarker><randomisation><randomization><randomly assigned><repository><risk stratification><screening><screenings><senior citizen><stratify risk><success><transcriptome><transcriptomics><translation research><translational investigation><transplant><twenty-one year old><twenty-one years of age><≥65 years>