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Review ArticleReview Article

Challenges and Opportunities for Childhood Cancer Drug Development

Peter J. Houghton and Raushan T. Kurmasheva
Michael M. Gottesman, ASSOCIATE EDITOR
Pharmacological Reviews October 2019, 71 (4) 671-697; DOI: https://doi.org/10.1124/pr.118.016972
Peter J. Houghton
Greehey Children’s Cancer Research Institute, University of Texas Health, San Antonio, Texas
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Raushan T. Kurmasheva
Greehey Children’s Cancer Research Institute, University of Texas Health, San Antonio, Texas
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Michael M. Gottesman
Roles: ASSOCIATE EDITOR
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  • Fig. 1.
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    Fig. 1.

    Changes in 5-year relative survival rates for the most prevalent cancers in children 0–14 years. Data show 5-year survival in from the period 1975 to 1977 (orange bars) and from 2006 to 2012 (blue bars) [adapted from Jemal et al. (2017) with permission].

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    Fig. 2.

    Genomic landscape of pediatric RMS highlighting candidate alterations. Demographic characteristics, histologic subtypes, and selected genes with copy number alterations or somatic mutations across 147 rhabdomyosarcoma cases. Unique sample identifier and sequencing platform. Sex, males in blue, females in pink. Age, years at diagnosis divided into less than 5 years and greater than 5 years. Histologic diagnosis, red, alveolar; blue, embryonal including spindle and botryoid subtypes; gray, RMS not otherwise specified. Mixed alveolar and embryonal histology in green. Copy number gains and losses for selected genes. Blue, losses; red, gains; green, loss of heterozygozity. Selected genes with somatic mutations. Purple, fusion protein; black, missense; orange, nonsense/splice site/indel mutations [from Shern et al. (2014) with permission].

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    Fig. 3.

    mSWI/SNF chromatin remodeling complexes in human cancer. Mammalian SWI/SNFcomplexes are separated into two separate forms: BRG1/BRM associated factor (BAF or SWI/SNF-A) and polybromo-associated BAF (PBAF or SWI/SNF-B). BAF and PBAF complexes share numerous subunits, including both ATPases BRG1 and BRM (depicted in red). BAF and PBAF differ from one another by incorporation of key peripheral subunits (depicted in green). Mutations in the genes encoding mSWI/SNF complex subunits are present in over 20% of human cancers, with specific subunits mutated in specific malignancies [from St Pierre and Kadoch (2017) with permission].

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    Fig. 4.

    Heat map representation of the activity of signaling inhibitors screened by the PPTP against sarcoma xenografts. Drugs are shown in the left column and sarcoma models in the top rows [from Geier et al. (2015) with permission].

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    Fig. 5.

    Objective response rates (ORR) were calculated for all tumor models tested for a particular drug (n = 1 to n = 55) for different studies, based upon the group median response. Red, responses predicted from a randomly chosen single mouse are plotted against group median response; blue, the single mouse ORR mean ORR correlation based on 1000 single mouse samples [from Murphy et al. (2016) with permission].

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    Fig. 6.

    Production of CAR-T cells in a GMP facility. Production begins with (1) leukapheresis of the patient and is then followed by selection of T cells (2), and their activation, from the leukapheresis product by positive selection with a CD3 antibody ± anti-CD28 antibody. After a few days the activated T cells are incubated with retroviral supernatant to transfer the CAR gene (3). Expansion, washing, and formulation result in infusion back into the patient [from Davila et al. (2014a) with permission].

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    Fig. 7.

    Constitutive broad (innate) expression of membranous programmed cell death 1 ligand 1 (PDL1) by tumor cells is thought to be driven by dysregulated signaling pathways such as PI3K-AKT, or chromosomal alterations and amplifications such as are found in Hodgkin lymphoma. In contrast, adaptive focal expression of PDL1 by tumor cells and macrophages occurs at the interface of tumor cell nests with immune infiltrates secreting pro-inflammatory factors such as interferon-γ (IFNγ; the “immune front”). The ligation of PDL1 with programmed cell death protein 1 (PD1) molecules will down-modulate T-cell function, essentially creating a negative feedback loop that dampens antitumour immunity. The innate and adaptive mechanisms for PDL1 induction are not mutually exclusive: constitutive oncogene-driven PDL1 expression may be further upregulated by inflammatory cytokines. In boxed insets, tumor cells are shown as blue, macrophages are purple, and T-cells are orange; black outlining of cells indicates PDL1 protein expression, such as would be demonstrated with immunohistochemistry [from Topalian et al. (2016) with permission].

Tables

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    TABLE 1

    Kinase rearrangement and therapeutic targets in Ph-like ALL. The TKIs shown are known or predicted to be active against rearrangements involving the listed kinase in experimental models but, with the exception of imatinib/dasatinib in EBF1-PDGFRB ALL, have not been shown to be effective in ALL [data from Roberts et al. (2014) and adapted from Mullighan (2014)].

    KinaseTKINo. of PartnersNo. of Cases5′ Genes
    ABL1Dasatinib614ETV6, NUP214, RCSD1, RANBP2, SNX2, ZMIZ1
    ABL2Dasatinib37PAG1, RCSD1, ZC3HAV1
    CSF1RDasatinib14SSBP2
    PDGFRBDasatinib411EBF1, SSBP2, TNIP1, ZEB2
    CRLF2JAK2 Inhibitor230IGH, P2RY8
    JAK2JAK2 Inhibitor1019ATF7IP, BCR, EBF1, ETV6, PAX5, PPFIBP1, SSBP2, STRN3, TERF2, TPR
    EPORJAK2 Inhibitor29IGH, IGK
    DGKHUnknown11ZFAND3
    IL2RBJAK1/3 inhibitor11MYH9
    NTRK3Crizotinib, LOXO-10111ETV6
    PTK2BFAK inhibitor21KDM6A
    TSLPJAK2 Inhibitor11IQGAP2
    TYK2TYK2 inhibitor11MYB
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    TABLE 2

    Common and novel recurrent translocations in soft tissue tumors

    TumorChromosome TranslocationFusion Transcript
    Ewing sarcoma/primitive neuroectodermal tumort(11;22)(q24;q12)FLI-EWS
    t(21;22)(q22;q12)ERG-EWS
    t(7;22)(p22;q12)ETV1-EWS
    t(17;22)(q12;q12)E1AF-EWS
    t(2;22)(q33;q12)FEV-EWS
    Desmoplastic round cell tumort(11;22)(p13;q12)WT1-EWS
    t(11;22)(q24;q12)FLI-EWS
    Synovial sarcomat(X;18)(p11.23;q11)SSX1-SYT
    t(X;18)(p11.21;q11)SSX2-SYT
    Alveolar rhabdomyosarcoma embryonal rhabdomyosarcoma spindle cell rhabdomyosarcomat(2;13)(q35;q14)PAX3-FOXO1
    t(1;13)(p36;q14)PAX7-FOXO1
    t(2;2)(q35;p23)PAX3-NCOA1a
    t(2;8)(q35;q13)PAX3-NCOA2a
    VGLL2-NCOA2a
    TEAD-NCOA2a
    t(2;8)(q35;q13)SRF-NCOA2a
    Clear cell sarcomat(12;22)(q13;q12)ATF1-EWS
    Myxoid liposarcomat(12;16)(q13;p11)CHOP-FUS
    t(12;22)(q13;q12)CHOP-EWS
    Extraskeletal myxoid chondrosarcomat(9;22)(q22;q12)CHN-EWS
    Dermatofibrosarcoma/giant cell fibrosarcomat(17;22)(q22;q13)COL1A1-PDGFB
    Congenital fibrosarcoma and mesoblastic nephromat(12;15)(p13;q25)ETV6-NTRK3
    Lipoblastomat(3;8)(q12;q11.2)PLAG1-HAS2
    t(7;8)(q31;q13)?
    Undifferentiated small round cell sarcomaT(4;19)(q35;q13.1) T(6;8)(p12;q11.2)CIC-DUX4a
    Undifferentiated (infants)T(10;19)(q26.3;q13) T(17;22)(q12;q12)EIAF-EWSa
    • ↵a Novel fusions [from Xiao et al. (2018)].

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Pharmacological Reviews: 71 (4)
Pharmacological Reviews
Vol. 71, Issue 4
1 Oct 2019
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Review ArticleReview Article

Pediatric Cancer Drug Development

Peter J. Houghton and Raushan T. Kurmasheva
Pharmacological Reviews October 1, 2019, 71 (4) 671-697; DOI: https://doi.org/10.1124/pr.118.016972

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Review ArticleReview Article

Pediatric Cancer Drug Development

Peter J. Houghton and Raushan T. Kurmasheva
Pharmacological Reviews October 1, 2019, 71 (4) 671-697; DOI: https://doi.org/10.1124/pr.118.016972
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  • Article
    • Abstract
    • I. Status of Therapy for Childhood Cancer
    • II. Genetics of Childhood Cancer: Dividing a Small Pie
    • III. Restrictions in Developing New Agents
    • IV. Selection of Agents
    • V. Humanized Mice for Immuno-Oncology
    • VI. Immuno-Oncology
    • VII. Strategies Going Forward
    • VIII. Summary
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