An Integrative Approach to Precision Cancer Medicine Using Patient-Derived Xenografts

Cho, Sung Yup; Kang, Wonyoung; Han, Jee Yun; Min, Seoyeon; Kang, Jeehoon; Lee, Ahra; Kwon, Jee Young; Lee, Charles; Park, Hansoo

doi:10.14348/molcells.2016.2350

Cited by 110 publications

(55 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 & 5). The outgrowth of the combination tumors may be due to heterogeneity either in RRM2 knockdown efficacy, where cells with less RRM2 knockdown grow out, or due to the inherent heterogeneity of patient-derived models (37, 38). Nonetheless, we had enough power for our biostatical approach to indicate a significant slowing of tumor growth in the combination (Fig.…”

Section: Discussionmentioning

confidence: 99%

Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma

Fatkhutdinov

Sproesser

Krepler

et al. 2016

Molecular Cancer Research

View full text Add to dashboard Cite

The majority of melanoma patients harbor mutations in the BRAF oncogene, thus making it a clinically relevant target. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression free survival of only 6–7 months. Previously, we reported high expression of ribonucleotide reductase M2 (RRM2), which is rate limiting for de novo dNTP synthesis, as a poor prognostic factor in mutant BRAF melanoma patients. In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed marked recurrence. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell cycle arrest.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma

Fatkhutdinov

Sproesser

Krepler

et al. 2016

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…A small piece of human whole tumor tissue is directly implanted into immunocompromised mice. Over time, the human stromal cells are replaced by mouse stromal cells (6–8); however, the exact timing and replacement of human to with murine stromal cells in human CRC is not clear (9). The loss of human cancer associated fibroblasts, endothelial cells, and immune cells over time has been characterized as a pitfall of the PDX model because mixed murine and human receptor-ligand signaling may alter the human cancer phenotype (9–11).…”

mentioning

confidence: 99%

Patient-derived Xenografts from Colorectal Carcinoma: A Temporal and Hierarchical Study of Murine Stromal Cell Replacement

Chao

Widen

Wood

et al. 2017

View full text Add to dashboard Cite

Background/Aim Patient-derived xenografting (PDX) of human colorectal cancer (CRC) is the preferred experimental model to study tumor response to therapeutic agents. Gradually, human stromal cells are replaced by mouse stromal cells; however, the exact timing of the replacement of human with murine stromal cells in human CRC xenograft has not been fully elucidated. We hypothesize that orthologous murine transcripts functionally substitutes for the loss due to replacement human stromal genes. Materials and Methods Human CRC were implanted in athymic nude mice in replicates and followed over time. Using next generation sequencing, we determined the temporal kinetics of human stromal cell replacement with the orthologous murine transcripts. Results CRC cell-induced re-organization of the normal, quiescent murine stromal cells into a protumorigenic phenotype supporting human CRC growth occurs at initial implantation. Conclusion Murine cell replacement occurs in the time- and size-dependent manner.

show abstract

“…However, the results of these studies do not necessarily reflect human clinical data [21], mainly because of the lack of a tumor microenvironment in such cell and tumor models. Moreover, studies in mice often are not directly applicable to human patients [22,23]. Therefore, it is necessary to establish animal models that better reflect human clinical pathology.…”

Section: Discussionmentioning

confidence: 99%

High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer

et al. 2020

View full text Add to dashboard Cite

Pancreatic cancer has an extremely poor prognosis, and identification of novel predictors of therapeutic efficacy and prognosis is urgently needed. Chemoresistance-related molecules are correlated with poor prognosis and may be effective targets for cancer treatment. Here, we aimed to identify novel molecules correlated with chemoresistance and poor prognosis in pancreatic cancer. We established 10 patient-derived xenograft (PDX) lines from patients with pancreatic cancer and performed next-generation sequencing (NGS) of tumor tissues from PDXs after treatment with standard drugs. We established a gene-transferred tumor cell line to express chemoresistance-related molecules and analyzed the chemoresistance of the established cell line against standard drugs. Finally, we performed immunohistochemical (IHC) analysis of chemoresistance-related molecules using 80 pancreatic cancer tissues. From NGS analysis, we identified olfactomedin-4 (OLFM4) as having high expression in the PDX group treated with anticancer drugs. In IHC analysis, OLFM4 expression was also high in PDXs administered anticancer drugs compared with that in untreated PDXs. Chemoresistance was observed by in vitro analysis of tumor cell lines with forced expression of OLFM4. In an assessment of tissue specimens from 80 patients with pancreatic cancer, Kaplan-Meier analysis showed that patients in the low OLFM4 expression group had a better survival rate than patients in the high OLFM4 expression group. Additionally, multivariate analysis showed that high expression of OLFM4 was an independent prognostic factor

show abstract

An Integrative Approach to Precision Cancer Medicine Using Patient-Derived Xenografts

Cited by 110 publications

References 74 publications

Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma

Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma

Patient-derived Xenografts from Colorectal Carcinoma: A Temporal and Hierarchical Study of Murine Stromal Cell Replacement

High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer

Contact Info

Product

Resources

About