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Precision Medicine in Pediatric Oncology

AndrewL.Kung,MD,PhDChairmanDepartmentofPediatrics

Advances in outcome for patients with pediatric cancers have come at a price

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CancerResearchUK

Cancer is the leading cause of disease-related death in

children

www.healthline.com

2/3 of survivors have long-term side effects

Identifying cancer causing mutations

1880’s 1980’s

Muta>onsresultinac>va>onofoncogenesorlossoftumorsuppressors

Cancercell

TheEncyclopediaBritannicahas300millionleIersTheamountofinforma>oninacell=10xEncyclopediaBritannicas

Normalcell

AGTCGAATTGCTCGATTGCTGGACACTTGGTCCTAGCTTAGCTAGCTAGGTTCTATCGTGACGTGTGTCACACGTAGCTGTACGTGAAACTGCTACGTTGTACGTACGTACTTTTCATTCGTACTGTATCTACTGACTGTTAGGGGCTATGCTGTACGGGGGGAGGGGAGCCACGATCGTCACACTGTCATGCGCGATGATCTGGTCGATCGTAGCTGTACGGGAGGGAGAG

Identifying cancer causing mutations

Cancercell

AGTCGAATTGCTCGATTGCTGGACACTTGGTCCTAGCTTAGCTAGCTAGGTTCTATCGTGACGTGTGTCACACGTAGCTGTACGTGAAACTGCTACGTTGTCCGTACGTACTTTTCATTCGTACTGTATCTACTGACTGTTAGGGGCTATGCTGTACGGGGGGAGGGGAGCCACGATCGTCACACTGTCATGCGCGATGATCTGGTCGATCGTAGCTGTACGGGAGGGAGAG

Eachcellhas3billionbasesofDNA!

Sequencing all 25,000 genes in the human genome

1990:HumanGenomeProject13years$3,000,000,000

Now:Days~$1,500

2009:SteveJobswasthe20thpersontohavehisgenomesequenced•  4ins>tu>ons(Stanford,

JHU,Harvard,Broad)•  6months•  $100,000

Actionable alterations: Directing patients to targeted therapies

5yoboywithAMLt(8;21)(q22;q22)AML1-ETO4cyclesofstandardAMLchemo

Relapse

URDbonemarrowtransplant

8months

Relapse

Day+100cKITAsn655Lys

LeukemiaNormal

TGAAGCTAC TGAATCTAC

MariaLuisaSulis

Salvagechemo

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Actionable alterations: Directing patients to targeted therapies

cKITAsn655Lys

LeukemiaNormal

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TGAAGCTAC TGAATCTAC

MariaLuisaSulis

What next? •  3yogirldiagnosedwith

abdominal“malignantpapillaryneoplasm”

•  Failedmul>plecyclesofsurgery,chemotherapy,radia>on,aIemptsatlocalcontrol

•  TransferredcaretoMSKCCat11yearsofage

Chemo:•  paclitaxel/carbopla>n•  gemcitabine/oxalipla>n•  paclitaxel/irinotecan•  irinotecan/temozolomide•  pazopanib•  rapamycin•  bevacizumab

Localcontrol:•  5debulkingsurgeries•  WholeabdomenXRT•  HIPEC•  IPchemo

8years

LAMTOR1-AKT1fusionEP53mutaIonTERTpromotermutaIon

IpataserIbCompassionateuse,1month

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MSKIMPACTWGSArcher

What next? •  8yogirldiagnosedwith

“fibroadenoma”andsubsequently“secretorybreastcarcinoma”

•  Failedmul>plecyclesofchemotherapyandsurgicalresec>ons

•  TransferredcaretoMSKCCat14yearsofage

Chemo:•  5FU/doxo/cyclophos•  carbo/docetaxel•  vinorelbine/gemcitabine•  ifos/doxo/decarbazine•  carbo/paclitaxel

Localcontrol:•  2lumpectomies•  mastectomy•  axillaryLNdissec>on•  2chestwallresec>ons

6years

ETV6-NTRK3fusionTERTpromotermutaIon

MSKIMPACTWGSArcher

LOXO-101Singlepa>entuse,1month

Precision medicine, personalized care

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FirstremissionwithMTX

Combina>onchemotherapy

Bonemarrowtransplanta>on

Risk-adaptedtherapy

Targetedtherapies

Sangersequencing

Humangenome

Nextgensequencing

Immuno-oncology

Strategic vision for Pediatrics • Createanexpansiveecosystemthatexpandsourreachandimpactforchildrenwithcancer:

–  Strengthenthe“Core”•  Restructuretoleverageauniquecareplatform•  Recruitnationalstatureservicechiefs•  Recruitleadershipandbuildaworldclasstranslationalresearchprogram•  Developapioneeringgenomics/geneticsprogram•  Addressbarrierstodrugaccess

–  Expandaccessandreach•  7day/weekclinic•  ExpandintoRegionalsites•  Establishstrategicpartnershipswithothercenters

2017 MSK Society Prize

NominationCommittee:–  AndrewKung–  RichardO’Reilly–  ScottArmstrong(DFCI)–  CharlieRoberts(St.Jude)– MignonLoh(UCSF) Dr.JimDowning

PresidentandCEO,St.JudeMSKCC,BoardofScien>ficConsultants

HOPP,ExternalAdvisoryBoard