Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs
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 th...
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| Format: | Article |
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MDPI AG
2019-06-01
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| Online Access: | https://www.mdpi.com/2073-4409/8/6/605 |
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| author | Simona Punzi Marine Meliksetian Laura Riva Federica Marocchi Giancarlo Pruneri Carmen Criscitiello Franco Orsi Lorenzo Spaggiari Monica Casiraghi Paolo Della Vigna Lucilla Luzi Giuseppe Curigliano Pier Giuseppe Pelicci Luisa Lanfrancone |
| author_facet | Simona Punzi Marine Meliksetian Laura Riva Federica Marocchi Giancarlo Pruneri Carmen Criscitiello Franco Orsi Lorenzo Spaggiari Monica Casiraghi Paolo Della Vigna Lucilla Luzi Giuseppe Curigliano Pier Giuseppe Pelicci Luisa Lanfrancone |
| author_sort | Simona Punzi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T18:55:43Z |
| format | Article |
| id | doaj.art-a1d7c223a11b43859ca723805ae5c21a |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T18:55:43Z |
| publishDate | 2019-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-a1d7c223a11b43859ca723805ae5c21a2023-08-02T06:56:42ZengMDPI AGCells2073-44092019-06-018660510.3390/cells8060605cells8060605Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXsSimona Punzi0Marine Meliksetian1Laura Riva2Federica Marocchi3Giancarlo Pruneri4Carmen Criscitiello5Franco Orsi6Lorenzo Spaggiari7Monica Casiraghi8Paolo Della Vigna9Lucilla Luzi10Giuseppe Curigliano11Pier Giuseppe Pelicci12Luisa Lanfrancone13Department of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyCenter for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyDepartment of Experimental Oncology, European Institute of Oncology IRCCS, 20139 Milan, ItalyHuman 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.https://www.mdpi.com/2073-4409/8/6/605breast cancerPDXoncogenic alterationspersonalized therapies |
| spellingShingle | Simona Punzi Marine Meliksetian Laura Riva Federica Marocchi Giancarlo Pruneri Carmen Criscitiello Franco Orsi Lorenzo Spaggiari Monica Casiraghi Paolo Della Vigna Lucilla Luzi Giuseppe Curigliano Pier Giuseppe Pelicci Luisa Lanfrancone Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs Cells breast cancer PDX oncogenic alterations personalized therapies |
| title | Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs |
| title_full | Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs |
| title_fullStr | Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs |
| title_full_unstemmed | Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs |
| title_short | Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs |
| title_sort | development of personalized therapeutic strategies by targeting actionable vulnerabilities in metastatic and chemotherapy resistant breast cancer pdxs |
| topic | breast cancer PDX oncogenic alterations personalized therapies |
| url | https://www.mdpi.com/2073-4409/8/6/605 |
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