The what, when, and why of human prostate cancer xenografts

Brennen, W. Nathaniel; Isaacs, John T.

doi:10.1002/pros.23510

Cited by 11 publications

(6 citation statements)

References 34 publications

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“…In conclusion, while it has been challenging to establish serially transplantable prostate cancer PDX models with a take rate that is at best in the 10‐40% range with a long latency time, there are now multiple prostate cancer PDX models available that can be used to advance our understanding of prostate cancer biology and help to identify new long‐term effective treatment strategies to conquer this disease. Detailed information about all models is provided in Tables and , and the investigator contact information for additional details and/or requests for collaborations is presented in Table .…”

Section: Resultsmentioning

confidence: 99%

Movember GAP1 PDX project: An international collection of serially transplantable prostate cancer patient‐derived xenograft (PDX) models

et al. 2018

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Section: Resultsmentioning

confidence: 99%

Movember GAP1 PDX project: An international collection of serially transplantable prostate cancer patient‐derived xenograft (PDX) models

et al. 2018

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“…Therefore, new and alternative approaches are currently being investigated to overcome or limit this clinically relevant behavior. Patientderived xenografts (PDX) have proven to be highly valuable tools for the development of precision medicine strategies for the study of PCa (7). BM18 and LAPC9 are bone metastatic PCa models with different molecular and histological features, with androgen-dependent and -independent growth, respectively (8,9).…”

Section: Introductionmentioning

confidence: 99%

Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity

et al. 2020

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Bone metastasis is the leading cause of prostate cancer (PCa) mortality, frequently marking the progression to castration-resistant PCa. Dysregulation of the androgen receptor pathway is a common feature of castration-resistant PCa, frequently appearing in association with mTOR pathway deregulations. Advanced PCa is also characterized by increased tumor heterogeneity and cancer stem cell (CSC) frequency. CSC-targeted therapy is currently being explored in advanced PCa, with the aim of reducing cancer clonal divergence and preventing disease progression. In this study, we compared the molecular pathways enriched in a set of bone metastasis from breast and prostate cancer from snap-frozen tissue. To further model PCa drug resistance mechanisms, we used two patient-derived xenografts (PDX) models of bone-metastatic PCa, BM18, and LAPC9. We developed in vitro organoids assay and ex vivo tumor slice drug assays to investigate the effects of mTOR- and CSC-targeting compounds. We found that both PDXs could be effectively targeted by treatment with the bivalent mTORC1/2 inhibitor Rapalink-1. Exposure of LAPC9 to Rapalink-1 but not to the CSC-targeting drug disulfiram blocked mTORC1/2 signaling, diminished expression of metabolic enzymes involved in glutamine and lipid metabolism and reduced the fraction of CD44+ and ALDEFluorhigh cells, in vitro. Mice treated with Rapalink-1 showed a significantly delayed tumor growth compared to control and cells recovered from the tumors of treated animals showed a marked decrease of CD44 expression. Taken together these results highlight the increased dependence of advanced PCa on the mTOR pathway, supporting the development of a targeted approach for advanced, bone metastatic PCa.

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“…PDXs have been shown to have relatively stable genomic alterations, but these characteristics can be changed, which might occur with each passage. Moreover, the take rates for establishing serial transplantable PDXs were relatively low, at 10% to 40% 72 . Thus, reliable and optimal preservation methods are greatly needed.…”

Section: Pdx Modelmentioning

confidence: 99%

Current experimental human tissue‐derived models for prostate cancer research

2020

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Scientists engaged in prostate cancer research have been conducting experiments using two‐dimensional cultures of prostate cancer cell lines for decades. However, these experiments fail to reproduce and reflect the clinical course of individual patients with prostate cancer, or the molecular and genetic characteristics of prostate cancer, the basic requirement for most of the preclinical studies on prostate cancer. The use of human prostate cancer tissues in experiments has enabled the collection and verification of clinically relevant data, including chemical reactions, changes in proteins, and specific gene expression. Tissue recombination models have been employed for studying prostate development, the initiation and progression of prostate cancer, and the tumor microenvironment. Notably, the epithelial–stromal interaction, which might play a critical role in prostate cancer pathogenesis, can be reproduced in this model. Patient‐derived xenograft models have been developed as powerful avatars comprising patient‐derived prostate cancer tissues implanted in immunocompromised mice and could serve as a precision medicine approach for each prostate cancer patient. Spheroid and organoid assays, representative of modern three‐dimensional cultures, can replicate the conditions in human prostate tumors and the prostate organ itself as a miniature model. Although an intact immune system against the tumor is missing from the models aimed at investigating immuno‐oncological reagents in various malignancies, all these experimental models can help researchers in developing new drugs and selecting appropriate treatment strategies for prostate cancer patients.

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The what, when, and why of human prostate cancer xenografts

Cited by 11 publications

References 34 publications

Movember GAP1 PDX project: An international collection of serially transplantable prostate cancer patient‐derived xenograft (PDX) models

Movember GAP1 PDX project: An international collection of serially transplantable prostate cancer patient‐derived xenograft (PDX) models

Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity

Current experimental human tissue‐derived models for prostate cancer research

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