A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches
Conventional treatment of dedifferentiated endometrial carcinoma (DEC)–an uncommon and highly aggressive uterine malignancy–is beset by high failure rates. A line of research that holds promise to overcome these limitations is tailored treatments targeted on specific molecular alterations. However,...
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MDPI AG
2021-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/23/5962 |
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| author | Chiao-Yun Lin Ren-Chin Wu Chen-Yang Huang Chyong-Huey Lai An-Shine Chao Hsin-Pai Li Chia-Lung Tsai Elizabeth Joo-Wen Kuek Cheng-Lung Hsu Angel Chao |
| author_facet | Chiao-Yun Lin Ren-Chin Wu Chen-Yang Huang Chyong-Huey Lai An-Shine Chao Hsin-Pai Li Chia-Lung Tsai Elizabeth Joo-Wen Kuek Cheng-Lung Hsu Angel Chao |
| author_sort | Chiao-Yun Lin |
| collection | DOAJ |
| description | Conventional treatment of dedifferentiated endometrial carcinoma (DEC)–an uncommon and highly aggressive uterine malignancy–is beset by high failure rates. A line of research that holds promise to overcome these limitations is tailored treatments targeted on specific molecular alterations. However, suitable preclinical platforms to allow a reliable implementation of this approach are still lacking. Here, we developed a patient-derived xenograft (PDX) model for preclinical testing of investigational drugs informed by molecular data. The model–termed PDX-mLung was established in mice implanted with lung metastatic lesions obtained from a patient with DEC. Histologic and whole-exome genetic analyses revealed a high degree of identity between PDX-mLung and the patient’s parental lesions (both primary DEC and lung metastases). Interestingly, molecular analyses revealed that PDX-mLung harbored druggable alterations including a <i>FGFR2</i> mutation and <i>CCNE2</i> amplification. Targeted combined treatment with the FGFR inhibitor lenvatinib and the cell cycle inhibitor palbociclib was found to exert synergistic therapeutic effects against in vivo tumor growth. Based on the results of RNA sequencing, lenvatinib and palbociclib were found to exert anti-tumor effects by interfering interferon signaling and activating hormonal pathways, respectively. Collectively, these data provide proof-of-concept evidence on the value of PDX models for preclinical testing of molecularly informed drug therapy in difficult-to-treat human malignancies. Further clinical research is needed to examine more rigorously the potential usefulness of the lenvatinib and palbociclib combination in patients with DEC. |
| first_indexed | 2024-03-10T04:56:48Z |
| format | Article |
| id | doaj.art-fb77d60497d64964bbadc9584d41560d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:56:48Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fb77d60497d64964bbadc9584d41560d2023-11-23T02:12:15ZengMDPI AGCancers2072-66942021-11-011323596210.3390/cancers13235962A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment ApproachesChiao-Yun Lin0Ren-Chin Wu1Chen-Yang Huang2Chyong-Huey Lai3An-Shine Chao4Hsin-Pai Li5Chia-Lung Tsai6Elizabeth Joo-Wen Kuek7Cheng-Lung Hsu8Angel Chao9Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan 333, TaiwanGynecologic Cancer Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, TaiwanDivision of Hematology-Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 333, TaiwanDepartment of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan 333, TaiwanDepartment of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan 333, TaiwanMolecular Medicine, Research Center, Department of Microbiology and Immunology, Chang Gung University, Taoyuan 333, TaiwanGenome Medicine Core Laboratory, Linkou Chang Gung Memorial Hospital, Taoyuan 333, TaiwanDivision of Hematology-Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 333, TaiwanDivision of Hematology-Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 333, TaiwanDepartment of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan 333, TaiwanConventional treatment of dedifferentiated endometrial carcinoma (DEC)–an uncommon and highly aggressive uterine malignancy–is beset by high failure rates. A line of research that holds promise to overcome these limitations is tailored treatments targeted on specific molecular alterations. However, suitable preclinical platforms to allow a reliable implementation of this approach are still lacking. Here, we developed a patient-derived xenograft (PDX) model for preclinical testing of investigational drugs informed by molecular data. The model–termed PDX-mLung was established in mice implanted with lung metastatic lesions obtained from a patient with DEC. Histologic and whole-exome genetic analyses revealed a high degree of identity between PDX-mLung and the patient’s parental lesions (both primary DEC and lung metastases). Interestingly, molecular analyses revealed that PDX-mLung harbored druggable alterations including a <i>FGFR2</i> mutation and <i>CCNE2</i> amplification. Targeted combined treatment with the FGFR inhibitor lenvatinib and the cell cycle inhibitor palbociclib was found to exert synergistic therapeutic effects against in vivo tumor growth. Based on the results of RNA sequencing, lenvatinib and palbociclib were found to exert anti-tumor effects by interfering interferon signaling and activating hormonal pathways, respectively. Collectively, these data provide proof-of-concept evidence on the value of PDX models for preclinical testing of molecularly informed drug therapy in difficult-to-treat human malignancies. Further clinical research is needed to examine more rigorously the potential usefulness of the lenvatinib and palbociclib combination in patients with DEC.https://www.mdpi.com/2072-6694/13/23/5962dedifferentiated endometrial carcinomapatient-derived xenograft modelstargeted treatmentproof-of-conceptlenvatinibpalbociclib |
| spellingShingle | Chiao-Yun Lin Ren-Chin Wu Chen-Yang Huang Chyong-Huey Lai An-Shine Chao Hsin-Pai Li Chia-Lung Tsai Elizabeth Joo-Wen Kuek Cheng-Lung Hsu Angel Chao A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches Cancers dedifferentiated endometrial carcinoma patient-derived xenograft models targeted treatment proof-of-concept lenvatinib palbociclib |
| title | A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches |
| title_full | A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches |
| title_fullStr | A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches |
| title_full_unstemmed | A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches |
| title_short | A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches |
| title_sort | patient derived xenograft model of dedifferentiated endometrial carcinoma a proof of concept study for the identification of new molecularly informed treatment approaches |
| topic | dedifferentiated endometrial carcinoma patient-derived xenograft models targeted treatment proof-of-concept lenvatinib palbociclib |
| url | https://www.mdpi.com/2072-6694/13/23/5962 |
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