UNLABELLED: In order to identify reasons for treatment failures when using targeted therapies, we have analyzed the comprehensive molecular profiles of three relapsed, poor-prognosis Burkitt lymphoma cases. All three cases had resembling clinical presentation and histology and all three patients relapsed, but their outcomes differed significantly. The samples of their tumor tissue were analyzed using whole-exome sequencing, gene expression profiling, phosphoproteomic assays, and single-cell phosphoflow cytometry. These results explain different treatment responses of the three histologically identical but molecularly different tumors. Our findings support a personalized approach for patient with high risk, refractory, and rare diseases and may contribute to personalized and customized treatment efforts for patients with limited treatment options like relapsed/refractory Burkitt lymphoma. SUMMARY: The main aim of this study is to analyze three relapsed Burkitt lymphoma patients using a comprehensive molecular profiling, in order to explain their different outcomes and to propose a biomarker-based targeted treatment. In cases 1 and 3, the tumor tissue and the host were analyzed prospectively and appropriate target for the treatment was successfully implemented; however, in case 2, analyses become available only retrospectively and his empirically based rescue treatment did not hit the right target of his disease.

Central European Institute of Technology Masaryk University Brno Czechia

Centre for Cardiovascular Surgery and Transplantation Brno Czechia

Childhood Leukaemia Investigation Prague Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University Prague Czechia

CSTS Health Care Toronto ON Canada

Department of Oncological Pathology Masaryk Memorial Cancer Institute Brno Czechia

Department of Pathology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czechia

Department of Pediatric Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czechia

Department of Pediatric Radiology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czechia

Department of Pediatric Surgery Orthopedics and Traumatology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czechia

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czechia

Faculty of Medicine Masaryk University Brno Czechia

International Clinical Research Center St Anne's University Hospital Brno Czechia

Laboratory of Tumor Biology Department of Experimental Biology Faculty of Science Masaryk University Brno Czechia

Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czechia

Zobrazit více v PubMed

Meinhardt A, Burkhardt B, Zimmermann M, Borkhardt A, Kontny U, Klingebiel T, et al. . Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-hodgkin's lymphoma and Burkitt leukemia. J Clin Oncol. (2010) 28:3115–21. 10.1200/JCO.2009.26.6791 PubMed DOI

Attarbaschi A, Dworzak M, Steiner M, Urban C, Fink FM, Reiter A, et al. . Outcome of children with primary resistant or relapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment: a population-based analysis of the Austrian cooperative study group. Pediatr Blood Cancer. (2005) 44:70–6. 10.1002/pbc.20121 PubMed DOI

R Core Team . A Language and Environment for Statistical Computing. R Foundation for Statistical Computing (2018).

Ahn T, Lee E, Huh N, Park T. Personalized identification of altered pathways in cancer using accumulated normal tissue data. Bioinformatics. (2014) 30:i422–9. 10.1093/bioinformatics/btu449 PubMed DOI PMC

Carvalho BS, Irizarry RA. A framework for oligonucleotide microarray preprocessing. Bioinformatics. (2010) 26:2363–7. 10.1093/bioinformatics/btq431 PubMed DOI PMC

Rietman EA, Scott JG, Tuszynski JA, Klement GL. Personalized anticancer therapy selection using molecular landscape topology and thermodynamics. Oncotarget. (2017) 8:18735–45. 10.18632/oncotarget.12932 PubMed DOI PMC

Skoda J, Neradil J, Zitterbart K, Sterba J, Veselska R. EGFR signaling in the HGG-02 glioblastoma cell line with an unusual loss of EGFR gene copy. Oncol Rep. (2014) 31:480–7. 10.3892/or.2013.2864 PubMed DOI

Kracker S, Curtis J, Ibrahim MA, Sediva A, Salisbury J, Campr V, et al. . Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome. J Allergy Clin Immunol. (2014) 134:233–6.e3. 10.1016/j.jaci.2014.02.020 PubMed DOI PMC

Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. . Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. (2014) 15:88–97. 10.1038/ni.2771 PubMed DOI PMC

Dan S, Okamura M, Seki M, Yamazaki K, Sugita H, Okui M, et al. . Correlating phosphatidylinositol 3-kinase inhibitor efficacy with signaling pathway status: in silico and biological evaluations. Cancer Res. (2010) 70:4982–94. 10.1158/0008-5472.CAN-09-4172 PubMed DOI

Jiménez-Ubieto A, Rodriguez A, Martinez Sánchez P, Gómez A, Rodriguez Y, Carreno-Tarragona G, et al. Fatal graftversus-host disease after allogeneic stem cell transplantation in a patient recently exposed to nivolumab. J Oncol Pharm Pract. (2019) 25:502–6. 10.1177/1078155217743069 PubMed DOI

Hlavackova E, Pilatova K, Cerna D, Selingerova I, Mudry P, Mazanek P, et al. . Dendritic cell-based immunotherapy in advanced sarcoma and neuroblastoma pediatric patients: anti-cancer treatment preceding monocyte harvest impairs the immunostimulatory and antigen-presenting behavior of dcs and manufacturing process outcome. Front Oncol. (2019) 9:1034. 10.3389/fonc.2019.01034 PubMed DOI PMC

Forrest DL, Hogge DE, Nevill TJ, Nantel SH, Barnett MJ, Shepherd JD, et al. High-dose therapy and autologous hematopoietic stem-cell transplantation does not increase the risk of second neoplasms for patients with Hodgkin's lymphoma: a comparison of conventional therapy alone versus conventional therapy followed by autologous hematopoietic stem-cell transplantation. J Clin Oncol. (2005) 23:7994–8002. 10.1200/JCO.2005.01.9083 PubMed DOI

Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. (2012) 26:1268–6. 10.1101/gad.190678.112 PubMed DOI PMC

Chen JY, Funk WD, Wright WE, Shay JW, Minna JD. Heterogeneity of transcriptional activity of mutant p53 proteins and p53 DNA target sequences. Oncogene. (1993) 8:2159–66. PubMed

Vaughan CA, Singh S, Windle B, Yeudall WA, Frum R, Grossman SR, et al. . Gain-of-function activity of mutant p53 in lung cancer through up-regulation of receptor protein tyrosine kinase Axl. Genes Cancer. (2012) 3:491–502. 10.1177/1947601912462719 PubMed DOI PMC

Odell AF, Odell LR, Askham JM, Alogheli H, Ponnambalam S, Hollstein M. A novel p53 mutant found in iatrogenic urothelial cancers is dysfunctional and can be rescued by a second-site global suppressor mutation. J Biol Chem. (2013) 288:16704–14. 10.1074/jbc.M112.443168 PubMed DOI PMC

Lin RK, Wu CY, Chang JW, Juan LJ, Hsu HS, Chen CY, et al. . Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res. (2010) 70:5807–17. 10.1158/0008-5472.CAN-09-4161 PubMed DOI

Kondo E, Tanaka T, Miyake T, Ichikawa T, Hirai M, Adachi M, et al. . Potent synergy of dual antitumor peptides for growth suppression of human glioblastoma cell lines. Mol Cancer Ther. (2008) 7:1461–71. 10.1158/1535-7163.MCT-07-2010 PubMed DOI

Smeenk L, van Heeringen SJ, Koeppel M, Gilbert B, Janssen-Megens E, Stunnenberg HG, et al. . Role of p53 serine 46 in p53 target gene regulation. PLoS ONE. (2011) 6:e17574. 10.1371/journal.pone.0017574 PubMed DOI PMC

Klement GL. Eco-evolution of cancer resistance. Sci Transl Med. (2016) 8:327fs5. 10.1126/scitranslmed.aaf3802 PubMed DOI

Simeone E, Grimaldi AM, Festino L, Vanella V, Palla M, Ascierto PA. Combination treatment of patients with BRAF-mutant melanoma: a new standard of care. BioDrugs. (2017) 31:51–61. 10.1007/s40259-016-0208-z PubMed DOI

Hu-Lieskovan S, Robert L, Homet Moreno B, Ribas A. Combining targeted therapy with immunotherapy in BRAF -mutant melanoma: promise and challenges. J Clin Oncol. (2014) 32:2248–54. 10.1200/JCO.2013.52.1377 PubMed DOI PMC

Sorge CE, McDaniel JK, Xavier AC. Targeted therapies for the treatment of pediatric non-hodgkin lymphomas: present and future. Pharmaceuticals. (2016) 9:28. 10.3390/ph9020028 PubMed DOI PMC

Eyre TA, Osborne WL, Gallop-Evans E, Ardeshna KM, Kassam S, Sadullah S, et al. . Results of a multicentre UK-wide compassionate use programme evaluating the efficacy of idelalisib monotherapy in relapsed, refractory follicular lymphoma. Br J Haematol. (2018) 181:555–9. 10.1111/bjh.14665 PubMed DOI

Davies A. Idelalisib for relapsed/refractory indolent B-cell non-Hodgkin's lymphoma: an overview of pharmacokinetics and clinical trial outcomes. Expert Rev Hematol. (2015) 8:581–93. 10.1586/17474086.2015.1071663 PubMed DOI

Egas-Bejar D, Anderson PM, Agarwal R, Corrales-Medina F, Devarajan E, Huh WW, et al. . Theranostic profiling for actionable aberrations in advanced high risk osteosarcoma with aggressive biology reveals high molecular diversity: the human fingerprint hypothesis. Oncoscience. (2014) 1:167–79. 10.18632/oncoscience.21 PubMed DOI PMC

Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. (2017) 377:62–70. 10.1056/NEJMra1510062 PubMed DOI

Schork NJ. Personalized medicine: time for one-person trials. Nature. (2015) 520:609–11. 10.1038/520609a PubMed DOI

Ogasawara T, Yasuyama M, Kawauchi K. Constitutive activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase in B-cell lymphoproliferative disorders. Int J Hematol. (2003) 77:364–70. 10.1007/BF02982645 PubMed DOI

Fuchs D, Berges C, Opelz G, Daniel V, Naujokat C. Increased expression and altered subunit composition of proteasomes induced by continuous proteasome inhibition establish apoptosis resistance and hyperproliferation of Burkitt lymphoma cells. J Cell Biochem. (2008) 103:270–83. 10.1002/jcb.21405 PubMed DOI

Kung C-P, Meckes DG, Raab-Traub N. Epstein-Barr Virus LMP1 activates EGFR, STAT3, and ERK through effects on PKC. J Virol. (2011) 85:4399–408. 10.1128/JVI.01703-10 PubMed DOI PMC

Huang YC, Lin SJ, Lin KM, Chou YC, Lin CW, Yu SC, et al. . Regulation of EBV LMP1-triggered EphA4 downregulation in EBV-associated B lymphoma and its impact on patients' survival. Blood. (2016) 128:1578–89. 10.1182/blood-2016-02-702530 PubMed DOI