Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia

Tea Pemovska; Mika Kontro; Bhagwan Yadav; Henrik Edgren; Samuli Eldfors; Agnieszka Szwajda; Henrikki Almusa; Maxim M Bespalov; Pekka Ellonen; Erkki Elonen; Bjørn T Gjertsen; Riikka Karjalainen; Evgeny Kulesskiy; Sonja Lagström; Anna Lehto; Maija Lepistö; Tuija Lundán; Muntasir Mamun Majumder; Jesus M Lopez Marti; Pirkko Mattila; Astrid Murumägi; Satu Mustjoki; Aino Palva; Alun Parsons; Tero Pirttinen; Maria E Rämet; Minna Suvela; Laura Turunen; Imre Västrik; Maija Wolf; Jonathan Knowles; Tero Aittokallio; Caroline A Heckman; Kimmo Porkka; Olli Kallioniemi; Krister Wennerberg

doi:10.1158/2159-8290.cd-13-0350

Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia

Tea Pemovska, Mika Kontro, Bhagwan Yadav, Henrik Edgren, Samuli Eldfors, Agnieszka Szwajda, Henrikki Almusa, Maxim M Bespalov, Pekka Ellonen, Erkki Elonen, Bjørn T Gjertsen, Riikka Karjalainen, Evgeny Kulesskiy, Sonja Lagström, Anna Lehto, Maija Lepistö, Tuija Lundán, Muntasir Mamun Majumder, Jesus M Lopez Marti, Pirkko MattilaAstrid Murumägi, Satu Mustjoki, Aino Palva, Alun Parsons, Tero Pirttinen, Maria E Rämet, Minna Suvela, Laura Turunen, Imre Västrik, Maija Wolf, Jonathan Knowles, Tero Aittokallio, Caroline A Heckman, Kimmo Porkka, Olli Kallioniemi, Krister Wennerberg

212 Citationer (Scopus)

Abstract

We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profiling and ex vivo drug sensitivity and resistance testing (DSRT) of patients' cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered five major taxonomic drug-response subtypes based on DSRT profiles, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3 -ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. After progression under DSRT-guided therapies, AML cells displayed significant clonal evolution and novel genomic changes potentially explaining resistance, whereas ex vivo DSRT data showed resistance to the clinically applied drugs and new vulnerabilities to previously ineffective drugs. SIGNIFICANCE: Here, we demonstrate an ISM strategy to optimize safe and effective personalized cancer therapies for individual patients as well as to understand and predict disease evolution and the next line of therapy. This approach could facilitate systematic drug repositioning of approved targeted drugs as well as help to prioritize and de-risk emerging drugs for clinical testing.

Originalsprog	Engelsk
Tidsskrift	Cancer Discovery
Vol/bind	3
Udgave nummer	12
Sider (fra-til)	1416-29
Antal sider	14
ISSN	2159-8274
DOI	https://doi.org/10.1158/2159-8290.cd-13-0350
Status	Udgivet - dec. 2013
Udgivet eksternt	Ja

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10.1158/2159-8290.cd-13-0350

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https://aacrjournals.org/cancerdiscovery/article-pdf/3/12/1416/1815903/1416.pdf

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Pemovska, T., Kontro, M., Yadav, B., Edgren, H., Eldfors, S., Szwajda, A., Almusa, H., Bespalov, M. M., Ellonen, P., Elonen, E., Gjertsen, B. T., Karjalainen, R., Kulesskiy, E., Lagström, S., Lehto, A., Lepistö, M., Lundán, T., Majumder, M. M., Marti, J. M. L., ... Wennerberg, K. (2013). Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia. Cancer Discovery, 3(12), 1416-29. https://doi.org/10.1158/2159-8290.cd-13-0350

Pemovska, T, Kontro, M, Yadav, B, Edgren, H, Eldfors, S, Szwajda, A, Almusa, H, Bespalov, MM, Ellonen, P, Elonen, E, Gjertsen, BT, Karjalainen, R, Kulesskiy, E, Lagström, S, Lehto, A, Lepistö, M, Lundán, T, Majumder, MM, Marti, JML, Mattila, P, Murumägi, A, Mustjoki, S, Palva, A, Parsons, A, Pirttinen, T, Rämet, ME, Suvela, M, Turunen, L, Västrik, I, Wolf, M, Knowles, J, Aittokallio, T, Heckman, CA, Porkka, K, Kallioniemi, O & Wennerberg, K 2013, 'Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia', Cancer Discovery, bind 3, nr. 12, s. 1416-29. https://doi.org/10.1158/2159-8290.cd-13-0350

@article{58794e7d80404a8aa93523ebe483e632,

title = "Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia",

abstract = "We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profiling and ex vivo drug sensitivity and resistance testing (DSRT) of patients' cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered five major taxonomic drug-response subtypes based on DSRT profiles, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3 -ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. After progression under DSRT-guided therapies, AML cells displayed significant clonal evolution and novel genomic changes potentially explaining resistance, whereas ex vivo DSRT data showed resistance to the clinically applied drugs and new vulnerabilities to previously ineffective drugs. SIGNIFICANCE: Here, we demonstrate an ISM strategy to optimize safe and effective personalized cancer therapies for individual patients as well as to understand and predict disease evolution and the next line of therapy. This approach could facilitate systematic drug repositioning of approved targeted drugs as well as help to prioritize and de-risk emerging drugs for clinical testing.",

keywords = "Antineoplastic Agents/pharmacology, Disease Progression, Drug Repositioning, Drug Resistance, Neoplasm/genetics, Gene Expression Profiling, Genome, Human, Humans, Leukemia, Myeloid, Acute/drug therapy, Precision Medicine/methods, Signal Transduction/drug effects, Treatment Outcome",

author = "Tea Pemovska and Mika Kontro and Bhagwan Yadav and Henrik Edgren and Samuli Eldfors and Agnieszka Szwajda and Henrikki Almusa and Bespalov, {Maxim M} and Pekka Ellonen and Erkki Elonen and Gjertsen, {Bj{\o}rn T} and Riikka Karjalainen and Evgeny Kulesskiy and Sonja Lagstr{\"o}m and Anna Lehto and Maija Lepist{\"o} and Tuija Lund{\'a}n and Majumder, {Muntasir Mamun} and Marti, {Jesus M Lopez} and Pirkko Mattila and Astrid Murum{\"a}gi and Satu Mustjoki and Aino Palva and Alun Parsons and Tero Pirttinen and R{\"a}met, {Maria E} and Minna Suvela and Laura Turunen and Imre V{\"a}strik and Maija Wolf and Jonathan Knowles and Tero Aittokallio and Heckman, {Caroline A} and Kimmo Porkka and Olli Kallioniemi and Krister Wennerberg",

note = "{\textcopyright}2013 AACR.",

year = "2013",

month = dec,

doi = "10.1158/2159-8290.cd-13-0350",

language = "English",

volume = "3",

pages = "1416--29",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research",

number = "12",

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TY - JOUR

T1 - Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia

AU - Pemovska, Tea

AU - Kontro, Mika

AU - Yadav, Bhagwan

AU - Edgren, Henrik

AU - Eldfors, Samuli

AU - Szwajda, Agnieszka

AU - Almusa, Henrikki

AU - Bespalov, Maxim M

AU - Ellonen, Pekka

AU - Elonen, Erkki

AU - Gjertsen, Bjørn T

AU - Karjalainen, Riikka

AU - Kulesskiy, Evgeny

AU - Lagström, Sonja

AU - Lehto, Anna

AU - Lepistö, Maija

AU - Lundán, Tuija

AU - Majumder, Muntasir Mamun

AU - Marti, Jesus M Lopez

AU - Mattila, Pirkko

AU - Murumägi, Astrid

AU - Mustjoki, Satu

AU - Palva, Aino

AU - Parsons, Alun

AU - Pirttinen, Tero

AU - Rämet, Maria E

AU - Suvela, Minna

AU - Turunen, Laura

AU - Västrik, Imre

AU - Wolf, Maija

AU - Knowles, Jonathan

AU - Aittokallio, Tero

AU - Heckman, Caroline A

AU - Porkka, Kimmo

AU - Kallioniemi, Olli

AU - Wennerberg, Krister

PY - 2013/12

Y1 - 2013/12

N2 - We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profiling and ex vivo drug sensitivity and resistance testing (DSRT) of patients' cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered five major taxonomic drug-response subtypes based on DSRT profiles, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3 -ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. After progression under DSRT-guided therapies, AML cells displayed significant clonal evolution and novel genomic changes potentially explaining resistance, whereas ex vivo DSRT data showed resistance to the clinically applied drugs and new vulnerabilities to previously ineffective drugs. SIGNIFICANCE: Here, we demonstrate an ISM strategy to optimize safe and effective personalized cancer therapies for individual patients as well as to understand and predict disease evolution and the next line of therapy. This approach could facilitate systematic drug repositioning of approved targeted drugs as well as help to prioritize and de-risk emerging drugs for clinical testing.

AB - We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profiling and ex vivo drug sensitivity and resistance testing (DSRT) of patients' cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered five major taxonomic drug-response subtypes based on DSRT profiles, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3 -ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. After progression under DSRT-guided therapies, AML cells displayed significant clonal evolution and novel genomic changes potentially explaining resistance, whereas ex vivo DSRT data showed resistance to the clinically applied drugs and new vulnerabilities to previously ineffective drugs. SIGNIFICANCE: Here, we demonstrate an ISM strategy to optimize safe and effective personalized cancer therapies for individual patients as well as to understand and predict disease evolution and the next line of therapy. This approach could facilitate systematic drug repositioning of approved targeted drugs as well as help to prioritize and de-risk emerging drugs for clinical testing.

KW - Antineoplastic Agents/pharmacology

KW - Disease Progression

KW - Drug Repositioning

KW - Drug Resistance, Neoplasm/genetics

KW - Gene Expression Profiling

KW - Genome, Human

KW - Humans

KW - Leukemia, Myeloid, Acute/drug therapy

KW - Precision Medicine/methods

KW - Signal Transduction/drug effects

KW - Treatment Outcome

U2 - 10.1158/2159-8290.cd-13-0350

DO - 10.1158/2159-8290.cd-13-0350

M3 - Journal article

C2 - 24056683

SN - 2159-8274

VL - 3

SP - 1416

EP - 1429

JO - Cancer Discovery

JF - Cancer Discovery

IS - 12

ER -

Individualized systems medicine strategy to tailor treatments for patients with chemorefractory acute myeloid leukemia

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