TY - JOUR
T1 - Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs
AU - Punzi, Simona
AU - Meliksetian, Marine
AU - Riva, Laura
AU - Marocchi, Federica
AU - Pruneri, Giancarlo
AU - Criscitiello, Carmen
AU - Orsi, Franco
AU - Spaggiari, Lorenzo
AU - Casiraghi, Monica
AU - Della Vigna, Paolo
AU - Luzi, Lucilla
AU - Curigliano, Giuseppe
AU - Pelicci, Pier Giuseppe
AU - Lanfrancone, Luisa
PY - 2019/6/18
Y1 - 2019/6/18
N2 - 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.
AB - 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.
KW - Animals
KW - Breast/metabolism
KW - Breast Neoplasms/genetics
KW - Disease Models, Animal
KW - Drug Resistance, Neoplasm/genetics
KW - Female
KW - Heterografts/metabolism
KW - Humans
KW - Mice
KW - Mice, Inbred NOD
KW - Neoplasm Metastasis/genetics
KW - Precision Medicine/methods
KW - Xenograft Model Antitumor Assays/methods
U2 - 10.3390/cells8060605
DO - 10.3390/cells8060605
M3 - Article
C2 - 31216647
VL - 8
JO - Cells
JF - Cells
SN - 2073-4409
IS - 6
ER -