Development of Novel Patient-Derived Preclinical Models from Malignant Effusions in Patients with Tyrosine Kinase Inhibitor–Resistant Clear Cell Renal Cell Carcinoma

Jiryeon Jang; Oliver Rath; Julia Schueler; Hyun Hwan Sung; Hwang Gyun Jeon; Byong Chang Jeong; Seong Il Seo; Seong Soo Jeon; Hyun Moo Lee; Han Yong Choi; Ghee Young Kwon; Woong Yang Park; Jeeyun Lee; Se Hoon Park

doi:10.1016/j.tranon.2017.01.016

Development of Novel Patient-Derived Preclinical Models from Malignant Effusions in Patients with Tyrosine Kinase Inhibitor–Resistant Clear Cell Renal Cell Carcinoma

Jiryeon Jang, Oliver Rath, Julia Schueler, Hyun Hwan Sung, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Moo Lee, Han Yong Choi, Ghee Young Kwon, Woong Yang Park, Jeeyun Lee, Se Hoon Park

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Abstract

PURPOSE: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood, and there is a need to develop new therapeutic options overcoming them. METHODS AND MATERIALS: To develop a preclinical model that predicts clinical activity of novel agents in 19 RCC patients, we established patient-derived cell (PDC) and xenograft (PDX) models derived from malignant effusions or surgical specimen. RESULTS: Successful PDCs, defined as cells that maintained growth following two passages, were established in 5 of 15 malignant effusions and 1 of 4 surgical specimens. One PDC, clinically refractory to TKIs, was implanted and engrafted in mice, resulting in a comparable histology to the primary tumor. The PDC-PDX model also showed similar genomic features when tested using targeted sequencing of cancer-related genes. When we examined the drug effects of the PDX model, the tumor cells showed resistance to TKIs and everolimus in vitro. CONCLUSION: The results suggest that the PDC-PDX preclinical model we developed using malignant effusions can be a useful preclinical model to interrogate sensitivity to targeted agents based on genomic alterations.

Original language	English
Pages (from-to)	304-310
Number of pages	7
Journal	Translational Oncology
Volume	10
Issue number	3
DOIs	https://doi.org/10.1016/j.tranon.2017.01.016
State	Published - Jun 2017
Externally published	Yes

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Jang, J., Rath, O., Schueler, J., Sung, H. H., Jeon, H. G., Jeong, B. C., Seo, S. I., Jeon, S. S., Lee, H. M., Choi, H. Y., Kwon, G. Y., Park, W. Y., Lee, J., & Park, S. H. (2017). Development of Novel Patient-Derived Preclinical Models from Malignant Effusions in Patients with Tyrosine Kinase Inhibitor–Resistant Clear Cell Renal Cell Carcinoma. Translational Oncology, 10(3), 304-310. https://doi.org/10.1016/j.tranon.2017.01.016

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title = "Development of Novel Patient-Derived Preclinical Models from Malignant Effusions in Patients with Tyrosine Kinase Inhibitor–Resistant Clear Cell Renal Cell Carcinoma",

abstract = "PURPOSE: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood, and there is a need to develop new therapeutic options overcoming them. METHODS AND MATERIALS: To develop a preclinical model that predicts clinical activity of novel agents in 19 RCC patients, we established patient-derived cell (PDC) and xenograft (PDX) models derived from malignant effusions or surgical specimen. RESULTS: Successful PDCs, defined as cells that maintained growth following two passages, were established in 5 of 15 malignant effusions and 1 of 4 surgical specimens. One PDC, clinically refractory to TKIs, was implanted and engrafted in mice, resulting in a comparable histology to the primary tumor. The PDC-PDX model also showed similar genomic features when tested using targeted sequencing of cancer-related genes. When we examined the drug effects of the PDX model, the tumor cells showed resistance to TKIs and everolimus in vitro. CONCLUSION: The results suggest that the PDC-PDX preclinical model we developed using malignant effusions can be a useful preclinical model to interrogate sensitivity to targeted agents based on genomic alterations.",

author = "Jiryeon Jang and Oliver Rath and Julia Schueler and Sung, \{Hyun Hwan\} and Jeon, \{Hwang Gyun\} and Jeong, \{Byong Chang\} and Seo, \{Seong Il\} and Jeon, \{Seong Soo\} and Lee, \{Hyun Moo\} and Choi, \{Han Yong\} and Kwon, \{Ghee Young\} and Park, \{Woong Yang\} and Jeeyun Lee and Park, \{Se Hoon\}",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = jun,

doi = "10.1016/j.tranon.2017.01.016",

language = "English",

volume = "10",

pages = "304--310",

journal = "Translational Oncology",

issn = "1936-5233",

number = "3",

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Jang, J, Rath, O, Schueler, J, Sung, HH , Jeon, HG , Jeong, BC , Seo, SI , Jeon, SS, Lee, HM, Choi, HY, Kwon, GY , Park, WY , Lee, J & Park, SH 2017, 'Development of Novel Patient-Derived Preclinical Models from Malignant Effusions in Patients with Tyrosine Kinase Inhibitor–Resistant Clear Cell Renal Cell Carcinoma', Translational Oncology, vol. 10, no. 3, pp. 304-310. https://doi.org/10.1016/j.tranon.2017.01.016

TY - JOUR

T1 - Development of Novel Patient-Derived Preclinical Models from Malignant Effusions in Patients with Tyrosine Kinase Inhibitor–Resistant Clear Cell Renal Cell Carcinoma

AU - Jang, Jiryeon

AU - Rath, Oliver

AU - Schueler, Julia

AU - Sung, Hyun Hwan

AU - Jeon, Hwang Gyun

AU - Jeong, Byong Chang

AU - Seo, Seong Il

AU - Jeon, Seong Soo

AU - Lee, Hyun Moo

AU - Choi, Han Yong

AU - Kwon, Ghee Young

AU - Park, Woong Yang

AU - Lee, Jeeyun

AU - Park, Se Hoon

PY - 2017/6

Y1 - 2017/6

N2 - PURPOSE: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood, and there is a need to develop new therapeutic options overcoming them. METHODS AND MATERIALS: To develop a preclinical model that predicts clinical activity of novel agents in 19 RCC patients, we established patient-derived cell (PDC) and xenograft (PDX) models derived from malignant effusions or surgical specimen. RESULTS: Successful PDCs, defined as cells that maintained growth following two passages, were established in 5 of 15 malignant effusions and 1 of 4 surgical specimens. One PDC, clinically refractory to TKIs, was implanted and engrafted in mice, resulting in a comparable histology to the primary tumor. The PDC-PDX model also showed similar genomic features when tested using targeted sequencing of cancer-related genes. When we examined the drug effects of the PDX model, the tumor cells showed resistance to TKIs and everolimus in vitro. CONCLUSION: The results suggest that the PDC-PDX preclinical model we developed using malignant effusions can be a useful preclinical model to interrogate sensitivity to targeted agents based on genomic alterations.

AB - PURPOSE: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood, and there is a need to develop new therapeutic options overcoming them. METHODS AND MATERIALS: To develop a preclinical model that predicts clinical activity of novel agents in 19 RCC patients, we established patient-derived cell (PDC) and xenograft (PDX) models derived from malignant effusions or surgical specimen. RESULTS: Successful PDCs, defined as cells that maintained growth following two passages, were established in 5 of 15 malignant effusions and 1 of 4 surgical specimens. One PDC, clinically refractory to TKIs, was implanted and engrafted in mice, resulting in a comparable histology to the primary tumor. The PDC-PDX model also showed similar genomic features when tested using targeted sequencing of cancer-related genes. When we examined the drug effects of the PDX model, the tumor cells showed resistance to TKIs and everolimus in vitro. CONCLUSION: The results suggest that the PDC-PDX preclinical model we developed using malignant effusions can be a useful preclinical model to interrogate sensitivity to targeted agents based on genomic alterations.

UR - https://www.scopus.com/pages/publications/85019168650

U2 - 10.1016/j.tranon.2017.01.016

DO - 10.1016/j.tranon.2017.01.016

M3 - Article

AN - SCOPUS:85019168650

SN - 1936-5233

VL - 10

SP - 304

EP - 310

JO - Translational Oncology

JF - Translational Oncology

IS - 3

ER -

Development of Novel Patient-Derived Preclinical Models from Malignant Effusions in Patients with Tyrosine Kinase Inhibitor–Resistant Clear Cell Renal Cell Carcinoma

Abstract

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