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


CONCLUSIONS
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.
1Institute for Molecular Medicine Finland, FIMM; 2Hematology Research Unit Helsinki, Helsinki University Central Hospital, University of Helsinki, Helsinki; 3Department of Clinical Chemistry and TYKSLAB, Turku University Central Hospital, University of Turku, Turku; 4Department of Internal Medicine, Tampere University Hospital, Tampere, Finland; 5Department of Clinical Science, Hematology Section, University of Bergen; and 6Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway.
Tea
T
Pemovska
Mika
M
Kontro
Bhagwan
B
Yadav
Henrik
H
Edgren
Samuli
S
Eldfors
Agnieszka
A
Szwajda
Henrikki
H
Almusa
Maxim M
MM
Bespalov
Pekka
P
Ellonen
Erkki
E
Elonen
Bjørn T
BT
Gjertsen
Riikka
R
Karjalainen
Evgeny
E
Kulesskiy
Sonja
S
Lagström
Anna
A
Lehto
Maija
M
Lepistö
Tuija
T
Lundán
Muntasir Mamun
MM
Majumder
Jesus M Lopez
JM
Marti
Pirkko
P
Mattila
Astrid
A
Murumägi
Satu
S
Mustjoki
Aino
A
Palva
Alun
A
Parsons
Tero
T
Pirttinen
Maria E
ME
Rämet
Minna
M
Suvela
Laura
L
Turunen
Imre
I
Västrik
Maija
M
Wolf
Jonathan
J
Knowles
Tero
T
Aittokallio
Caroline A
CA
Heckman
Kimmo
K
Porkka
Olli
O
Kallioniemi
Krister
K
Wennerberg
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D058492:Drug Repositioning; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D057285:Precision Medicine / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
D000970:Antineoplastic Agents