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Prospective use of the single-mouse experimental design for the evaluation of PLX038A

  • Samson Ghilu
  • Qilin Li
  • Shaun D. Fontaine
  • Daniel V. Santi
  • Raushan T. Kurmasheva
  • Siyuan Zheng
  • Peter J. HoughtonEmail author
Original Article

Abstract

Purpose

Defining robust criteria for drug activity in preclinical studies allows for fewer animals per treatment group, and potentially allows for inclusion of additional cancer models that more accurately represent genetic diversity and, potentially, allows for tumor sensitivity biomarker identification.

Methods

Using a single-mouse design, 32 pediatric xenograft tumor models representing diverse pediatric cancer types [Ewing sarcoma (9), brain (4), rhabdomyosarcoma (10), Wilms tumor (4), and non-CNS rhabdoid tumors (5)] were evaluated for response to a single administration of pegylated-SN38 (PLX038A), a controlled-release PEGylated formulation of SN-38. Endpoints measured were percent tumor regression, and event-free survival (EFS). The correlation between response to PLX038A was compared to that for ten models treated with irinotecan (2.5 mg/kg × 5 days × 2 cycles), using a traditional design (10 mice/group). Correlations between tumor sensitivity, genetic mutations and gene expression were sought. Models showing no disease at week 20 were categorized as ‘extreme responders’ to PLX038A, whereas those with EFS less than 5 weeks were categorized as ‘resistant’.

Results

The activity of PLX038A was evaluable in 31/32 models. PLX038A induced > 50% volume regressions in 25 models (78%). Initial tumor volume regression correlated only modestly with EFS (r2 = 0.238), but sensitivity to PLX038A was better correlated with response to irinotecan when one tumor hypersensitive to PLX038A was omitted (r2 = 0.6844). Mutations in 53BP1 were observed in three of six sensitive tumor models compared to none in resistant models (n = 6).

Conclusions

This study demonstrates the feasibility of using a single-mouse design for assessing the antitumor activity of an agent, while encompassing greater genetic diversity representative of childhood cancers. PLX038A was highly active in most xenograft models, and tumor sensitivity to PLX038A was correlated with sensitivity to irinotecan, validating the single-mouse design in identifying agents with the same mechanism of action. Biomarkers that correlated with model sensitivity included wild-type TP53, or mutant TP53 but with a mutation in 53BP1, thus a defect in DNA damage response. These results support the value of the single-mouse experimental design.

Keywords

Drug evaluation Alternative experimental design Single mouse study Response criteria Pediatric cancer Genetic diversity 

Notes

Funding

This work was funded in part by USPHS award UO1CA199297, CA169368 and CA165995 (PJH) from NCI and CPRIT PR170055 (SZ).

Compliance with ethical standards

Conflict of interest

S. Ghilu declares that he has no conflict of interest. Q. Li declares that he has no conflict of interest. S. D. Fontaine is an employee and holds stock in Prolynx. D. V. Santi is an employee and holds stock in Prolynx. R. T. Kurmasheva declares that she has no conflict of interest. S. Zheng declares that he has no conflict of interest. P. J. Houghton declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants.

Supplementary material

280_2019_4017_MOESM1_ESM.tif (1.9 mb)
Supplementary file1 (TIF 1937 kb) DNA mismatch repair (left) and replication (right) pathways are up regulated in the models resistant to PLX038A treatment. These GSEA results show more genes of each pathway are highly expressed in the resistant tumors (towards the blue bar). Each line in the figure represents the relative ranking of a pathway gene in the resistant vs sensitive comparison

References

  1. 1.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247.  https://doi.org/10.1016/j.ejca.2008.10.026 CrossRefPubMedGoogle Scholar
  2. 2.
    Houghton PJ, Morton CL, Tucker C, Payne D, Favours E, Cole C, Gorlick R, Kolb EA, Zhang W, Lock R, Carol H, Tajbakhsh M, Reynolds CP, Maris JM, Courtright J, Keir ST, Friedman HS, Stopford C, Zeidner J, Wu J, Liu T, Billups CA, Khan J, Ansher S, Zhang J, Smith MA (2007) The pediatric preclinical testing program: description of models and early testing results. Pediatr Blood Cancer 49(7):928–940.  https://doi.org/10.1002/pbc.21078 CrossRefPubMedGoogle Scholar
  3. 3.
    Shern JF, Chen L, Chmielecki J, Wei JS, Patidar R, Rosenberg M, Ambrogio L, Auclair D, Wang J, Song YK, Tolman C, Hurd L, Liao H, Zhang S, Bogen D, Brohl AS, Sindiri S, Catchpoole D, Badgett T, Getz G, Mora J, Anderson JR, Skapek SX, Barr FG, Meyerson M, Hawkins DS, Khan J (2014) Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov 4(2):216–231.  https://doi.org/10.1158/2159-8290.CD-13-0639 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Brohl AS, Solomon DA, Chang W, Wang J, Song Y, Sindiri S, Patidar R, Hurd L, Chen L, Shern JF, Liao H, Wen X, Gerard J, Kim JS, Lopez Guerrero JA, Machado I, Wai DH, Picci P, Triche T, Horvai AE, Miettinen M, Wei JS, Catchpool D, Llombart-Bosch A, Waldman T, Khan J (2014) The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet 10(7):e1004475.  https://doi.org/10.1371/journal.pgen.1004475 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hwang EI, Kool M, Burger PC, Capper D, Chavez L, Brabetz S, Williams-Hughes C, Billups C, Heier L, Jaju A, Michalski J, Li Y, Leary S, Zhou T, von Deimling A, Jones DTW, Fouladi M, Pollack IF, Gajjar A, Packer RJ, Pfister SM, Olson JM (2018) Extensive molecular and clinical heterogeneity in patients with histologically diagnosed CNS-PNET treated as a single entity: a report from the children’s oncology group randomized ACNS0332 trial. J Clin Oncol.  https://doi.org/10.1200/JCO.2017.76.4720 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J, Schouten-van Meeteren A, van Vuurden D, Clifford SC, Pietsch T, von Bueren AO, Rutkowski S, McCabe M, Collins VP, Backlund ML, Haberler C, Bourdeaut F, Delattre O, Doz F, Ellison DW, Gilbertson RJ, Pomeroy SL, Taylor MD, Lichter P, Pfister SM (2012) Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, group 3, and group 4 medulloblastomas. Acta Neuropathol 123(4):473–484.  https://doi.org/10.1007/s00401-012-0958-8 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Pajtler KW, Witt H, Sill M, Jones DT, Hovestadt V, Kratochwil F, Wani K, Tatevossian R, Punchihewa C, Johann P, Reimand J, Warnatz HJ, Ryzhova M, Mack S, Ramaswamy V, Capper D, Schweizer L, Sieber L, Wittmann A, Huang Z, van Sluis P, Volckmann R, Koster J, Versteeg R, Fults D, Toledano H, Avigad S, Hoffman LM, Donson AM, Foreman N, Hewer E, Zitterbart K, Gilbert M, Armstrong TS, Gupta N, Allen JC, Karajannis MA, Zagzag D, Hasselblatt M, Kulozik AE, Witt O, Collins VP, von Hoff K, Rutkowski S, Pietsch T, Bader G, Yaspo ML, von Deimling A, Lichter P, Taylor MD, Gilbertson R, Ellison DW, Aldape K, Korshunov A, Kool M, Pfister SM (2015) Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27(5):728–743.  https://doi.org/10.1016/j.ccell.2015.04.002 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Oberthuer A, Hero B, Berthold F, Juraeva D, Faldum A, Kahlert Y, Asgharzadeh S, Seeger R, Scaruffi P, Tonini GP, Janoueix-Lerosey I, Delattre O, Schleiermacher G, Vandesompele J, Vermeulen J, Speleman F, Noguera R, Piqueras M, Benard J, Valent A, Avigad S, Yaniv I, Weber A, Christiansen H, Grundy RG, Schardt K, Schwab M, Eils R, Warnat P, Kaderali L, Simon T, Decarolis B, Theissen J, Westermann F, Brors B, Fischer M (2010) Prognostic impact of gene expression-based classification for neuroblastoma. J Clin Oncol 28(21):3506–3515.  https://doi.org/10.1200/JCO.2009.27.3367 CrossRefPubMedGoogle Scholar
  9. 9.
    Oberthuer A, Juraeva D, Hero B, Volland R, Sterz C, Schmidt R, Faldum A, Kahlert Y, Engesser A, Asgharzadeh S, Seeger R, Ohira M, Nakagawara A, Scaruffi P, Tonini GP, Janoueix-Lerosey I, Delattre O, Schleiermacher G, Vandesompele J, Speleman F, Noguera R, Piqueras M, Benard J, Valent A, Avigad S, Yaniv I, Grundy RG, Ortmann M, Shao C, Schwab M, Eils R, Simon T, Theissen J, Berthold F, Westermann F, Brors B, Fischer M (2015) Revised risk estimation and treatment stratification of low- and intermediate-risk neuroblastoma patients by integrating clinical and molecular prognostic markers. Clin Cancer Res 21(8):1904–1915.  https://doi.org/10.1158/1078-0432.CCR-14-0817 CrossRefPubMedGoogle Scholar
  10. 10.
    Murphy B, Yin H, Maris JM, Kolb EA, Gorlick R, Reynolds CP, Kang MH, Keir ST, Kurmasheva RT, Dvorchik I, Wu J, Billups CA, Boateng N, Smith MA, Lock RB, Houghton PJ (2016) Evaluation of alternative in vivo drug screening methodology: a single mouse analysis. Cancer Res 76(19):5798–5809.  https://doi.org/10.1158/0008-5472.CAN-16-0122 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Northcott PA, Dubuc AM, Pfister S, Taylor MD (2012) Molecular subgroups of medulloblastoma. Expert Rev Neurother 12(7):871–884.  https://doi.org/10.1586/ern.12.66 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gao H, Korn JM, Ferretti S, Monahan JE, Wang Y, Singh M, Zhang C, Schnell C, Yang G, Zhang Y, Balbin OA, Barbe S, Cai H, Casey F, Chatterjee S, Chiang DY, Chuai S, Cogan SM, Collins SD, Dammassa E, Ebel N, Embry M, Green J, Kauffmann A, Kowal C, Leary RJ, Lehar J, Liang Y, Loo A, Lorenzana E, Robert McDonald E 3rd, McLaughlin ME, Merkin J, Meyer R, Naylor TL, Patawaran M, Reddy A, Roelli C, Ruddy DA, Salangsang F, Santacroce F, Singh AP, Tang Y, Tinetto W, Tobler S, Velazquez R, Venkatesan K, Von Arx F, Wang HQ, Wang Z, Wiesmann M, Wyss D, Xu F, Bitter H, Atadja P, Lees E, Hofmann F, Li E, Keen N, Cozens R, Jensen MR, Pryer NK, Williams JA, Sellers WR (2015) High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat Med 21(11):1318–1325.  https://doi.org/10.1038/nm.3954 CrossRefPubMedGoogle Scholar
  13. 13.
    Santi DV, Schneider EL, Ashley GW (2014) Macromolecular prodrug that provides the irinotecan (CPT-11) active-metabolite SN-38 with ultralong half-life, low C(max), and low glucuronide formation. J Med Chem 57(6):2303–2314.  https://doi.org/10.1021/jm401644v CrossRefPubMedGoogle Scholar
  14. 14.
    Santi DV, Schneider EL, Reid R, Robinson L, Ashley GW (2012) Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates. Proc Natl Acad Sci USA 109(16):6211–6216.  https://doi.org/10.1073/pnas.1117147109 CrossRefPubMedGoogle Scholar
  15. 15.
    Pappo AS, Lyden E, Breitfeld P, Donaldson SS, Wiener E, Parham D, Crews KR, Houghton P, Meyer WH, Children’s Oncology G (2007) Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the children’s oncology group. J Clin Oncol 25(4):362–369.  https://doi.org/10.1200/JCO.2006.07.1720 CrossRefPubMedGoogle Scholar
  16. 16.
    Weigel BJ, Lyden E, Anderson JR, Meyer WH, Parham DM, Rodeberg DA, Michalski JM, Hawkins DS, Arndt CA (2016) Intensive multiagent therapy, including dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, irinotecan, and radiation, in patients with high-risk rhabdomyosarcoma: a report from the children’s oncology group. J Clin Oncol 34(2):117–122.  https://doi.org/10.1200/JCO.2015.63.4048 CrossRefPubMedGoogle Scholar
  17. 17.
    Kolb EA, Gorlick R, Houghton PJ, Morton CL, Neale G, Keir ST, Carol H, Lock R, Phelps D, Kang MH, Reynolds CP, Maris JM, Billups C, Smith MA (2010) Initial testing (stage 1) of AZD6244 (ARRY-142886) by the pediatric preclinical testing program. Pediatr Blood Cancer 55(4):668–677.  https://doi.org/10.1002/pbc.22576 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Saraf AJ, Elhawary G, Finlay JL, Scott S, Olshefski R, Halverson M, Boue DR, AbdelBaki MS (2018) Complete remission of an extracranially disseminated anaplastic pleomorphic xanthoastrocytoma with everolimus: a case report and literature review. Pediatr Neurol 88:65–70.  https://doi.org/10.1016/j.pediatrneurol.2018.09.004 CrossRefPubMedGoogle Scholar
  19. 19.
    Fontaine SD, Hann B, Reid R, Ashley GW, Santi DV (2019) Species-specific optimization of PEG~SN-38 prodrug pharmacokinetics and antitumor effects in a triple-negative BRCA1-deficient xenograft. Cancer Chemother Pharmacol 84(4):729–738.  https://doi.org/10.1007/s00280-019-03903-5 CrossRefPubMedGoogle Scholar
  20. 20.
    Rokita JL, Rathi KS, Cardenas MF, Upton KA, Jayaseelan J, Cross KL, Pfeil J, Egolf LE, Way GP, Farrel A, Kendsersky NM, Patel K, Gaonkar KS, Modi A, Berko ER, Lopez G, Vaksman Z, Mayoh C, Nance J, McCoy K, Haber M, Evans K, McCalmont H, Bendak K, Bohm JW, Marshall GM, Tyrrell V, Kalletla K, Braun FK, Qi L, Du Y, Zhang H, Lindsay HB, Zhao S, Shu J, Baxter P, Morton C, Kurmashev D, Zheng S, Chen Y, Bowen J, Bryan AC, Leraas KM, Coppens SE, Doddapaneni H, Momin Z, Zhang W, Sacks GI, Hart LS, Krytska K, Mosse YP, Gatto GJ, Sanchez Y, Greene CS, Diskin SJ, Vaske OM, Haussler D, Gastier-Foster JM, Kolb EA, Gorlick R, Li XN, Reynolds CP, Kurmasheva RT, Houghton PJ, Smith MA, Lock RB, Raman P, Wheeler DA, Maris JM (2019) Genomic profiling of childhood tumor patient-derived xenograft models to enable rational clinical trial design. Cell Rep 29(6):1675–1689.  https://doi.org/10.1016/j.celrep.2019.09.071 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G (2011) GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol 12(4):R41.  https://doi.org/10.1186/gb-2011-12-4-r41 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550.  https://doi.org/10.1073/pnas.0506580102 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sokolowski E, Turina CB, Kikuchi K, Langenau DM, Keller C (2014) Proof-of-concept rare cancers in drug development: the case for rhabdomyosarcoma. Oncogene 33(15):1877–1889.  https://doi.org/10.1038/onc.2013.129 CrossRefPubMedGoogle Scholar
  24. 24.
    Lalloo AK, Luo FR, Guo A, Paranjpe PV, Lee SH, Vyas V, Rubin E, Sinko PJ (2004) Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1) and multidrug resistance protein 2 (ABCC2). BMC Med 2:16.  https://doi.org/10.1186/1741-7015-2-16 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lin F, Marchetti S, Pluim D, Iusuf D, Mazzanti R, Schellens JH, Beijnen JH, van Tellingen O (2013) Abcc4 together with abcb1 and abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues. Clin Cancer Res 19(8):2084–2095.  https://doi.org/10.1158/1078-0432.CCR-12-3105 CrossRefPubMedGoogle Scholar
  26. 26.
    Rokita JL, Rathi KS, Cardenas MF, Upton KA, Jayaseelan J, Cross KL, Pfeil J, Egolf LE, Way GP, Farrel A, Kendsersky NM, Patel K, Gaonkar KS, Modi A, Berko ER, Lopez G, Vaksman Z, Mayoh C, Nance J, McCoy K, Haber M, Evans K, McCalmont H, Bendak K, Böhm JW, Marshall GM, Tyrrell V, Kalletla K, Braun FK, Qi L, Du Y, Zhang H, Lindsay HB, Zhao S, Shu J, Baxter P, Morton C, Kurmashev D, Zheng S, Chen Y, Bowen J, Bryan AC, Leraas KM, Coppens SE, Doddapaneni H, Momin Z, Zhang W, Sacks GI, Hart LS, Krytska K, Mosse YP, Gatto GJ, Sanchez Y, Greene CS, Diskin SJ, Vaske OM, Haussler D, Gastier-Foster JM, Kolb EA, Gorlick R, Li XN, Reynolds CP, Kurmasheva RT, Houghton PJ, Smith MA, Lock RB, Raman P, Wheeler DA, Maris JM (2019) Genomic profiling of childhood tumor patient-derived xenograft models to enable rational clinical trialdesign. Cell Rep 29(6):1675–1689.e9.  https://doi.org/10.1016/j.celrep.2019.09.071 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ma X, Liu Y, Liu Y, Alexandrov LB, Edmonson MN, Gawad C, Zhou X, Li Y, Rusch MC, Easton J, Huether R, Gonzalez-Pena V, Wilkinson MR, Hermida LC, Davis S, Sioson E, Pounds S, Cao X, Ries RE, Wang Z, Chen X, Dong L, Diskin SJ, Smith MA, Guidry Auvil JM, Meltzer PS, Lau CC, Perlman EJ, Maris JM, Meshinchi S, Hunger SP, Gerhard DS, Zhang J (2018) Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature 555(7696):371–376.  https://doi.org/10.1038/nature25795 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M, Wang L, Soda M, Kikuchi A, Igarashi T, Nakagawara A, Hayashi Y, Mano H, Ogawa S (2008) Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455(7215):971–974.  https://doi.org/10.1038/nature07399 CrossRefPubMedGoogle Scholar
  29. 29.
    Janoueix-Lerosey I, Lequin D, Brugieres L, Ribeiro A, de Pontual L, Combaret V, Raynal V, Puisieux A, Schleiermacher G, Pierron G, Valteau-Couanet D, Frebourg T, Michon J, Lyonnet S, Amiel J, Delattre O (2008) Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455(7215):967–970.  https://doi.org/10.1038/nature07398 CrossRefPubMedGoogle Scholar
  30. 30.
    Eleveld TF, Oldridge DA, Bernard V, Koster J, Colmet Daage L, Diskin SJ, Schild L, Bentahar NB, Bellini A, Chicard M, Lapouble E, Combaret V, Legoix-Ne P, Michon J, Pugh TJ, Hart LS, Rader J, Attiyeh EF, Wei JS, Zhang S, Naranjo A, Gastier-Foster JM, Hogarty MD, Asgharzadeh S, Smith MA, Guidry Auvil JM, Watkins TB, Zwijnenburg DA, Ebus ME, van Sluis P, Hakkert A, van Wezel E, van der Schoot CE, Westerhout EM, Schulte JH, Tytgat GA, Dolman ME, Janoueix-Lerosey I, Gerhard DS, Caron HN, Delattre O, Khan J, Versteeg R, Schleiermacher G, Molenaar JJ, Maris JM (2015) Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet 47(8):864–871.  https://doi.org/10.1038/ng.3333 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kieran MW (2014) Targeted treatment for sonic hedgehog-dependent medulloblastoma. Neuro Oncol 16(8):1037–1047.  https://doi.org/10.1093/neuonc/nou109 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kieran MW (2014) Targeting BRAF in pediatric brain tumors. Am Soc Clin Oncol Educ Book 34:e436–e440.  https://doi.org/10.14694/EdBook_AM.2014.34.e436 CrossRefGoogle Scholar
  33. 33.
    Banerjee A, Jakacki RI, Onar-Thomas A, Wu S, Nicolaides T, Young Poussaint T, Fangusaro J, Phillips J, Perry A, Turner D, Prados M, Packer RJ, Qaddoumi I, Gururangan S, Pollack IF, Goldman S, Doyle LA, Stewart CF, Boyett JM, Kun LE, Fouladi M (2017) A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro Oncol 19(8):1135–1144.  https://doi.org/10.1093/neuonc/now282 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Fangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, Banerjee A, Packer RJ, Kilburn LB, Goldman S, Pollack IF, Qaddoumi I, Jakacki RI, Fisher PG, Dhall G, Baxter P, Kreissman SG, Stewart CF, Jones DTW, Pfister SM, Vezina G, Stern JS, Panigrahy A, Patay Z, Tamrazi B, Jones JY, Haque SS, Enterline DS, Cha S, Fisher MJ, Doyle LA, Smith M, Dunkel IJ, Fouladi M (2019) Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol 20(7):1011–1022.  https://doi.org/10.1016/S1470-2045(19)30277-3 CrossRefPubMedGoogle Scholar
  35. 35.
    Ooms AH, Gadd S, Gerhard DS, Smith MA, Guidry Auvil JM, Meerzaman D, Chen QR, Hsu CH, Yan C, Nguyen C, Hu Y, Ma Y, Zong Z, Mungall AJ, Moore RA, Marra MA, Huff V, Dome JS, Chi YY, Tian J, Geller JI, Mullighan CG, Ma J, Wheeler DA, Hampton OA, Walz AL, van den Heuvel-Eibrink MM, de Krijger RR, Ross N, Gastier-Foster JM, Perlman EJ (2016) Significance of TP53 mutation in wilms tumors with diffuse anaplasia: a report from the children’s oncology group. Clin Cancer Res 22(22):5582–5591.  https://doi.org/10.1158/1078-0432.CCR-16-0985 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Bardeesy N, Falkoff D, Petruzzi MJ, Nowak N, Zabel B, Adam M, Aguiar MC, Grundy P, Shows T, Pelletier J (1994) Anaplastic Wilms’ tumour, a subtype displaying poor prognosis, harbours p53 gene mutations. Nat Genet 7(1):91–97.  https://doi.org/10.1038/ng0594-91 CrossRefPubMedGoogle Scholar
  37. 37.
    Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Ji R, Zhang P, Mookerjee B, Legos J, Kefford R, Dummer R, Kirkwood JM (2017) Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 377(19):1813–1823.  https://doi.org/10.1056/NEJMoa1708539 CrossRefPubMedGoogle Scholar
  38. 38.
    Fiskus W, Mitsiades N (2016) B-raf inhibition in the clinic: present and future. Annu Rev Med 67:29–43.  https://doi.org/10.1146/annurev-med-090514-030732 CrossRefPubMedGoogle Scholar
  39. 39.
    Houdaihed L, Evans JC, Allen C (2017) Overcoming the road blocks: advancement of block copolymer micelles for cancer therapy in the clinic. Mol Pharm 14(8):2503–2517.  https://doi.org/10.1021/acs.molpharmaceut.7b00188 CrossRefPubMedGoogle Scholar
  40. 40.
    Maeda H (2012) Macromolecular therapeutics in cancer treatment: the EPR effect and beyond. J Control Release 164(2):138–144.  https://doi.org/10.1016/j.jconrel.2012.04.038 CrossRefPubMedGoogle Scholar
  41. 41.
    Gokduman K (2016) Strategies targeting DNA topoisomerase I in cancer chemotherapy: camptothecins, nanocarriers for camptothecins, organic non-camptothecin compounds and metal complexes. Curr Drug Targets 17(16):1928–1939CrossRefGoogle Scholar
  42. 42.
    Kaufmann SH (1998) Cell death induced by topoisomerase-targeted drugs: more questions than answers. Biochim Biophys Acta 1400(1–3):195–211CrossRefGoogle Scholar
  43. 43.
    Wagner LM (2015) Fifteen years of irinotecan therapy for pediatric sarcoma: where to next? Clin Sarcoma Res 5:20.  https://doi.org/10.1186/s13569-015-0035-x CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Metzger ML, Stewart CF, Freeman BB 3rd, Billups CA, Hoffer FA, Wu J, Coppes MJ, Grant R, Chintagumpala M, Mullen EA, Alvarado C, Daw NC, Dome JS (2007) Topotecan is active against wilms’ tumor: results of a multi-institutional phase II study. J Clin Oncol 25(21):3130–3136.  https://doi.org/10.1200/JCO.2007.10.9298 CrossRefPubMedGoogle Scholar
  45. 45.
    Furman WL, Stewart CF, Kirstein M, Kepner JL, Bernstein ML, Kung F, Vietti TJ, Steuber CP, Becton DL, Baruchel S, Pratt C (2002) Protracted intermittent schedule of topotecan in children with refractory acute leukemia: a pediatric oncology group study. J Clin Oncol 20(6):1617–1624.  https://doi.org/10.1200/JCO.2002.20.6.1617 CrossRefPubMedGoogle Scholar
  46. 46.
    Daw NC, Anderson JR, Hoffer FA, Geller JI, Kalapurakal JA, Perlman EJ (2017) A phase 2 study of vincristine and irinotecan in metastatic diffuse anaplastic wilms tumor: results from the children’s oncology group AREN0321 study. J Clin Oncol 32(suppl 15):10032Google Scholar
  47. 47.
    Palmerini E, Jones RL, Setola E, Picci P, Marchesi E, Luksch R, Grignani G, Cesari M, Longhi A, Abate ME, Paioli A, Szucs Z, D'Ambrosio L, Scotlandi K, Fagioli F, Asaftei S, Ferrari S (2018) Irinotecan and temozolomide in recurrent ewing sarcoma: an analysis in 51 adult and pediatric patients. Acta Oncol 57(7):958–964.  https://doi.org/10.1080/0284186X.2018.1449250 CrossRefPubMedGoogle Scholar
  48. 48.
    Rose WC, Wild R (2004) Therapeutic synergy of oral taxane BMS-275183 and cetuximab versus human tumor xenografts. Clin Cancer Res 10(21):7413–7417.  https://doi.org/10.1158/1078-0432.CCR-04-1045 CrossRefPubMedGoogle Scholar
  49. 49.
    Yoo E, Kim BU, Lee SY, Cho CH, Chung JH, Lee CH (2005) 53BP1 is associated with replication protein A and is required for RPA2 hyperphosphorylation following DNA damage. Oncogene 24(35):5423–5430.  https://doi.org/10.1038/sj.onc.1208710 CrossRefPubMedGoogle Scholar
  50. 50.
    Houghton PJ, Stewart CF, Zamboni WC, Thompson J, Luo X, Danks MK, Houghton JA (1996) Schedule-dependent efficacy of camptothecins in models of human cancer. Ann N Y Acad Sci 803:188–201.  https://doi.org/10.1111/j.1749-6632.1996.tb26388.x CrossRefPubMedGoogle Scholar
  51. 51.
    Houghton PJ, Cheshire PJ, Hallman JC, Bissery MC, Mathieu-Boue A, Houghton JA (1993) Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against human tumor xenografts: lack of cross-resistance in vivo in tumors with acquired resistance to the topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin. Cancer Res 53(12):2823–2829PubMedGoogle Scholar
  52. 52.
    Stewart CF, Leggas M, Schuetz JD, Panetta JC, Cheshire PJ, Peterson J, Daw N, Jenkins JJ 3rd, Gilbertson R, Germain GS, Harwood FC, Houghton PJ (2004) Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. Cancer Res 64(20):7491–7499.  https://doi.org/10.1158/0008-5472.CAN-04-0096 CrossRefPubMedGoogle Scholar
  53. 53.
    Furman WL, Navid F, Daw NC, McCarville MB, McGregor LM, Spunt SL, Rodriguez-Galindo C, Panetta JC, Crews KR, Wu J, Gajjar AJ, Houghton PJ, Santana VM, Stewart CF (2009) Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors. J Clin Oncol 27(27):4599–4604.  https://doi.org/10.1200/JCO.2008.19.6642 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Grobner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, Johann PD, Balasubramanian GP, Segura-Wang M, Brabetz S, Bender S, Hutter B, Sturm D, Pfaff E, Hubschmann D, Zipprich G, Heinold M, Eils J, Lawerenz C, Erkek S, Lambo S, Waszak S, Blattmann C, Borkhardt A, Kuhlen M, Eggert A, Fulda S, Gessler M, Wegert J, Kappler R, Baumhoer D, Burdach S, Kirschner-Schwabe R, Kontny U, Kulozik AE, Lohmann D, Hettmer S, Eckert C, Bielack S, Nathrath M, Niemeyer C, Richter GH, Schulte J, Siebert R, Westermann F, Molenaar JJ, Vassal G, Witt H, Project IP-S, Project IM-S, Burkhardt B, Kratz CP, Witt O, van Tilburg CM, Kramm CM, Fleischhack G, Dirksen U, Rutkowski S, Fruhwald M, von Hoff K, Wolf S, Klingebiel T, Koscielniak E, Landgraf P, Koster J, Resnick AC, Zhang J, Liu Y, Zhou X, Waanders AJ, Zwijnenburg DA, Raman P, Brors B, Weber UD, Northcott PA, Pajtler KW, Kool M, Piro RM, Korbel JO, Schlesner M, Eils R, Jones DTW, Lichter P, Chavez L, Zapatka M, Pfister SM (2018) The landscape of genomic alterations across childhood cancers. Nature 555(7696):321–327.  https://doi.org/10.1038/nature25480 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • Samson Ghilu
    • 1
  • Qilin Li
    • 1
  • Shaun D. Fontaine
    • 2
  • Daniel V. Santi
    • 2
  • Raushan T. Kurmasheva
    • 1
  • Siyuan Zheng
    • 1
  • Peter J. Houghton
    • 1
    Email author
  1. 1.Greehey Children’s Cancer Research InstituteUT Health San AntonioSan AntonioUSA
  2. 2.ProLynx LLCSouth San FranciscoUSA

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