Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Viktoras Frismantas, Maria Pamela Dobay, Anna Rinaldi, Joelle Tchinda, Samuel H. Dunn, Joachim Kunz, Paulina Richter-Pechanska, Blerim Marovca, Orrin Pail, Silvia Jenni, Ernesto Diaz-Flores, Bill Chang, Timothy J. Brown, Robert H. Collins, Sebastian Uhrig, Gnana P. Balasubramanian, Obul R. Bandapalli, Salome Higi, Sabrina Eugster, Pamela VoegeliMauro Delorenzi, Gunnar Cario, Mignon L. Loh, Martin Schrappe, Martin Stanulla, Andreas E. Kulozik, Martina U. Muckenthaler, Vaskar Saha, Julie A. Irving, Roland Meisel, Thomas Radimerski, Arend Von Stackelberg, Cornelia Eckert, Jeffrey Tyner, Peter Horvath, Beat C. Bornhauser, Jean Pierre Bourquin

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information andachieved a 5-month remission. Thus, drug profiling captures disease-relevant featuresand unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.

Original languageEnglish (US)
Pages (from-to)e26-e37
JournalBlood
Volume129
Issue number11
DOIs
StatePublished - Mar 16 2017

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Leukemia
Pharmaceutical Preparations
T-cells
Coculture Techniques
T-Lymphocytes
Drug Resistance
Heterografts
Cell Cycle
Drug Repositioning
Cells
B-Lymphoid Precursor Cells
Refractory materials
Vincristine
Mesenchymal Stromal Cells
Dexamethasone
Biomarkers
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Frismantas, V., Dobay, M. P., Rinaldi, A., Tchinda, J., Dunn, S. H., Kunz, J., ... Bourquin, J. P. (2017). Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. Blood, 129(11), e26-e37. https://doi.org/10.1182/blood-2016-09-738070

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. / Frismantas, Viktoras; Dobay, Maria Pamela; Rinaldi, Anna; Tchinda, Joelle; Dunn, Samuel H.; Kunz, Joachim; Richter-Pechanska, Paulina; Marovca, Blerim; Pail, Orrin; Jenni, Silvia; Diaz-Flores, Ernesto; Chang, Bill; Brown, Timothy J.; Collins, Robert H.; Uhrig, Sebastian; Balasubramanian, Gnana P.; Bandapalli, Obul R.; Higi, Salome; Eugster, Sabrina; Voegeli, Pamela; Delorenzi, Mauro; Cario, Gunnar; Loh, Mignon L.; Schrappe, Martin; Stanulla, Martin; Kulozik, Andreas E.; Muckenthaler, Martina U.; Saha, Vaskar; Irving, Julie A.; Meisel, Roland; Radimerski, Thomas; Von Stackelberg, Arend; Eckert, Cornelia; Tyner, Jeffrey; Horvath, Peter; Bornhauser, Beat C.; Bourquin, Jean Pierre.

In: Blood, Vol. 129, No. 11, 16.03.2017, p. e26-e37.

Research output: Contribution to journalArticle

Frismantas, V, Dobay, MP, Rinaldi, A, Tchinda, J, Dunn, SH, Kunz, J, Richter-Pechanska, P, Marovca, B, Pail, O, Jenni, S, Diaz-Flores, E, Chang, B, Brown, TJ, Collins, RH, Uhrig, S, Balasubramanian, GP, Bandapalli, OR, Higi, S, Eugster, S, Voegeli, P, Delorenzi, M, Cario, G, Loh, ML, Schrappe, M, Stanulla, M, Kulozik, AE, Muckenthaler, MU, Saha, V, Irving, JA, Meisel, R, Radimerski, T, Von Stackelberg, A, Eckert, C, Tyner, J, Horvath, P, Bornhauser, BC & Bourquin, JP 2017, 'Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia', Blood, vol. 129, no. 11, pp. e26-e37. https://doi.org/10.1182/blood-2016-09-738070
Frismantas, Viktoras ; Dobay, Maria Pamela ; Rinaldi, Anna ; Tchinda, Joelle ; Dunn, Samuel H. ; Kunz, Joachim ; Richter-Pechanska, Paulina ; Marovca, Blerim ; Pail, Orrin ; Jenni, Silvia ; Diaz-Flores, Ernesto ; Chang, Bill ; Brown, Timothy J. ; Collins, Robert H. ; Uhrig, Sebastian ; Balasubramanian, Gnana P. ; Bandapalli, Obul R. ; Higi, Salome ; Eugster, Sabrina ; Voegeli, Pamela ; Delorenzi, Mauro ; Cario, Gunnar ; Loh, Mignon L. ; Schrappe, Martin ; Stanulla, Martin ; Kulozik, Andreas E. ; Muckenthaler, Martina U. ; Saha, Vaskar ; Irving, Julie A. ; Meisel, Roland ; Radimerski, Thomas ; Von Stackelberg, Arend ; Eckert, Cornelia ; Tyner, Jeffrey ; Horvath, Peter ; Bornhauser, Beat C. ; Bourquin, Jean Pierre. / Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. In: Blood. 2017 ; Vol. 129, No. 11. pp. e26-e37.
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abstract = "Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information andachieved a 5-month remission. Thus, drug profiling captures disease-relevant featuresand unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.",
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AU - Dobay, Maria Pamela

AU - Rinaldi, Anna

AU - Tchinda, Joelle

AU - Dunn, Samuel H.

AU - Kunz, Joachim

AU - Richter-Pechanska, Paulina

AU - Marovca, Blerim

AU - Pail, Orrin

AU - Jenni, Silvia

AU - Diaz-Flores, Ernesto

AU - Chang, Bill

AU - Brown, Timothy J.

AU - Collins, Robert H.

AU - Uhrig, Sebastian

AU - Balasubramanian, Gnana P.

AU - Bandapalli, Obul R.

AU - Higi, Salome

AU - Eugster, Sabrina

AU - Voegeli, Pamela

AU - Delorenzi, Mauro

AU - Cario, Gunnar

AU - Loh, Mignon L.

AU - Schrappe, Martin

AU - Stanulla, Martin

AU - Kulozik, Andreas E.

AU - Muckenthaler, Martina U.

AU - Saha, Vaskar

AU - Irving, Julie A.

AU - Meisel, Roland

AU - Radimerski, Thomas

AU - Von Stackelberg, Arend

AU - Eckert, Cornelia

AU - Tyner, Jeffrey

AU - Horvath, Peter

AU - Bornhauser, Beat C.

AU - Bourquin, Jean Pierre

PY - 2017/3/16

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N2 - Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information andachieved a 5-month remission. Thus, drug profiling captures disease-relevant featuresand unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.

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