Functional and genomic characterization of patient‐derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma

Sakamoto, Hiromasa; Yamasaki, Toshinari; Sumiyoshi, Takayuki; Takeda, Masatoshi; Shibasaki, Noboru; Utsunomiya, Noriaki; Arakaki, Ryuichiro; Akamatsu, Shusuke; Kobayashi, Takashi; Inoue, Takahiro; Kamba, Tomomi; Nakamura, Eijiro; Ogawa, Osamu

doi:10.1002/cam4.3578

Cited by 5 publications

(4 citation statements)

References 67 publications

(130 reference statements)

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“…We established PDX and PDX-BF for patients with clear cell carcinoma. Studies have also been published on PDX from clear cell carcinoma in cervical cancer and renal cancer [45,46]. According to Serebrenik et al, PDX from ovarian clear cell carcinoma had histologically similar characteristics to primary tumors [47].…”

Section: Discussionmentioning

confidence: 99%

Creation and Validation of Patient-Derived Cancer Model Using Peritoneal and Pleural Effusion in Patients with Advanced Ovarian Cancer: An Early Experience

Nishie,

Tanaka,

Hirosuna

et al. 2024

JCM

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Background: The application of personalized cancer treatment based on genetic information and surgical samples has begun in the field of cancer medicine. However, a biopsy may be painful for patients with advanced diseases that do not qualify for surgical resection. Patient-derived xenografts (PDXs) are cancer models in which patient samples are transplanted into immunodeficient mice. PDXs are expected to be useful for personalized medicine. The aim of this study was to establish a PDX from body fluid (PDX-BF), such as peritoneal and pleural effusion samples, to provide personalized medicine without surgery. Methods: PDXs-BF were created from patients with ovarian cancer who had positive cytology findings based on peritoneal and pleural effusion samples. PDXs were also prepared from each primary tumor. The pathological findings based on immunohistochemistry were compared between the primary tumor, PDX, and PDX-BF. Further, genomic profiles and gene expression were evaluated using DNA and RNA sequencing to compare primary tumors, PDXs, and PDX-BF. Results: Among the 15 patients, PDX-BF was established for 8 patients (5 high-grade serous carcinoma, 1 carcinosarcoma, 1 low-grade serous carcinoma, and 1 clear cell carcinoma); the success rate was 53%. Histologically, PDXs-BF have features similar to those of primary tumors and PDXs. In particular, PDXs-BF had similar gene mutations and expression patterns to primary tumors and PDXs. Conclusions: PDX-BF reproduced primary tumors in terms of pathological features and genomic profiles, including gene mutation and expression. Thus, PDX-BF may be a potential alternative to surgical resection for patients with advanced disease.

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Section: Discussionmentioning

confidence: 99%

Creation and Validation of Patient-Derived Cancer Model Using Peritoneal and Pleural Effusion in Patients with Advanced Ovarian Cancer: An Early Experience

Nishie,

Tanaka,

Hirosuna

et al. 2024

JCM

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“…Our data indicated that targeting the activity of ZDHHC2 could further inhibit the AKT signaling axis, thereby improving the sensitivity of ccRCC to TKIs and mTOR inhibitors. Moreover, a variety of factors confer resistance to mTOR inhibitors in renal cancer, such as HIF-mediated suppression of DEPTOR ( 62 ), aberrant expression of PTEN ( 63 ), and decreased DNMT1 enzyme activity ( 64 ). After long-term use of mTOR inhibitors leads to drug resistance, targeting ZDHHC2 can be used as a complementary and alternative therapy in ccRCC.…”

Section: Discussionmentioning

confidence: 99%

ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma

et al. 2023

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Tyrosine kinase inhibitors (TKIs) that can suppress the VEGF signaling pathway and angiogenesis have been developed to impede the progression of malignant tumors and have been approved as first-line targeted agents for clear cell renal cell carcinoma (ccRCC). Dysregulation of lipid metabolism is a major driver of TKI resistance in renal cancer. In this study, we showed that the palmitoyl acyltransferase ZDHHC2 is abnormally upregulated in tissues and cell lines resistant to TKIs, such as sunitinib. Upregulation of ZDHHC2 contributed to sunitinib resistance in cells and mice, and ZDHHC2 regulated angiogenesis and cell proliferation in ccRCC. Mechanistically, ZDHHC2 mediated AGK S-palmitoylation to promote translocation of AGK into the plasma membrane and activation of the PI3K-AKT-mTOR signaling pathway in ccRCC, which modulated sunitinib sensitivity. In conclusion, these results identify a ZDHHC2-AGK signaling axis and suggest that ZDHHC2 is a targetable candidate for improving the anti-tumor efficacy of sunitinib in ccRCC.

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“…To date, reports on OC have mainly focused on high-grade serous carcinoma. Studies have also been published on PDX from clear cell carcinoma in cervical cancer and renal cancer (33,34).…”

Section: Discussionmentioning

confidence: 99%

Creation and validation of a patient-derived cancer model using peritoneal and pleural effusion samples from patients with ovarian cancer

Nishie

Tanaka

Murakami

et al. 2023

Preprint

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Background: The application of personalized cancer treatment based on genetic information and surgical samples has begun in the field of cancer medicine. However, biopsy may be painful for patients with advanced disease that do not qualify for surgical resection. Patient-derived xenografts (PDXs) are cancer models in which patient samples are transplanted into immunodeficient mice. PDXs are expected to be useful for personalized medicine. The aim of this study was to establish a PDX from body fluid (PDX-BF), such as peritoneal and pleural effusion samples,to provide personalized medicine without surgery. Methods PDXs-BF were created from patients with ovarian cancer who had positive cytology findings based on peritoneal and pleural effusion samples. PDXs were also prepared from each primary tumor. The pathological findings based on immunohistochemistry were compared between the primary tumor, PDX, and PDX-BF. Further, genomic profiles and gene expression were evaluated using DNA and RNA sequencing to compare primary tumors, PDXs, and PDX-BF. Results Among the 15 patients, PDX-BF was established for 8 patients (5 high-grade serous carcinoma, 1 carcinosarcoma, 1 low-grade serous carcinoma, and 1 clear cell carcinoma); the successrate was 53%. Histologically, PDXs-BF have features similar to those of primary tumors and PDXs. In particular, PDXs-BF had similar gene mutations and expression patterns to primary tumors and PDXs. Conclusions PDX-BF reproduced primary tumors in terms of pathological features and genomic profiles, including gene mutation and expression. Thus, PDX-BF may be a potential alternative to surgical resection for patients with advanced disease.

show abstract

Functional and genomic characterization of patient‐derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma

Cited by 5 publications

References 67 publications

Creation and Validation of Patient-Derived Cancer Model Using Peritoneal and Pleural Effusion in Patients with Advanced Ovarian Cancer: An Early Experience

Creation and Validation of Patient-Derived Cancer Model Using Peritoneal and Pleural Effusion in Patients with Advanced Ovarian Cancer: An Early Experience

ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma

Creation and validation of a patient-derived cancer model using peritoneal and pleural effusion samples from patients with ovarian cancer

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