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Cells. 2019 Jun 18;8(6). pii: E605. doi: 10.3390/cells8060605.

Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs.

Author information

1
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. simona.punzi@ieo.it.
2
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. marine.meliksetyan@ieo.it.
3
Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, Italy. lr15@sanger.ac.uk.
4
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. lr15@sanger.ac.uk.
5
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. federica.marocchi@ieo.it.
6
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. giancarlo.pruneri@istitutotumori.mi.it.
7
Department of Oncology and Hemato-Oncology, University of Milano, 20140 Milan, Italy. giancarlo.pruneri@istitutotumori.mi.it.
8
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. carmen.criscitiello@ieo.it.
9
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. franco.orsi@ieo.it.
10
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. lorenzo.spaggiari@ieo.it.
11
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. monica.casiraghi@ieo.it.
12
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. paolo.dellavigna@ieo.it.
13
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. lucilla.luzi@ieo.it.
14
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. giuseppe.curigliano@ieo.it.
15
Department of Oncology and Hemato-Oncology, University of Milano, 20140 Milan, Italy. giuseppe.curigliano@ieo.it.
16
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. piergiuseppe.pelicci@ieo.it.
17
Department of Oncology and Hemato-Oncology, University of Milano, 20140 Milan, Italy. piergiuseppe.pelicci@ieo.it.
18
Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, Italy. luisa.lanfrancone@ieo.it.

Abstract

Human breast cancer is characterized by a high degree of inter-patients heterogeneity in terms of histology, genomic alterations, gene expression patterns, and metastatic behavior, which deeply influences individual prognosis and treatment response. The main cause of mortality in breast cancer is the therapy-resistant metastatic disease, which sets the priority for novel treatment strategies for these patients. In the present study, we demonstrate that Patient Derived Xenografts (PDXs) that were obtained from metastatic and therapy-resistant breast cancer samples recapitulate the wide spectrum of the disease in terms of histologic subtypes and mutational profiles, as evaluated by whole exome sequencing. We have integrated genomic and transcriptomic data to identify oncogenic and actionable pathways in each PDX. By taking advantage of primary short-term in vitro cultures from PDX tumors, we showed their resistance to standard chemotherapy (Paclitaxel), as seen in the patients. Moreover, we selected targeting drugs and analyzed PDX sensitivity to single agents or to combination of targeted and standard therapy on the basis of PDX-specific genomic or transcriptomic alterations. Our data demonstrate that PDXs represent a suitable model to test new targeting drugs or drug combinations and to prioritize personalized therapeutic regimens for pre-clinal and clinical tests.

KEYWORDS:

PDX; breast cancer; oncogenic alterations; personalized therapies

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