Patient‐derived xenografts for individualized care in advanced sarcoma

Stebbing, Justin; Paz, Keren; Schwartz, Gary K.; Wexler, Leonard H.; Maki, Robert G.; Pollock, Raphael E.; Morris, Ronnie; Cohen, Richard; Shankar, Arjun; Blackman, Glen; Harding, Victoria; Vásquez, David; Krell, Jonathan; Ciznadija, Daniel; Katz, Amanda; Sidransky, David

doi:10.1002/cncr.28696

Cited by 150 publications

(146 citation statements)

References 25 publications

Supporting

Mentioning

143

Contrasting

Order By: Relevance

“…67 ) have developed protocols and networks to generate clinical trial-associated xenografts (CTAXs) (TABLE 1). These advanced PDX models are currently being derived from image-guided biopsy samples taken at different time points during disease progression and following new lines of treatment in the context of clinical trials.…”

mentioning

confidence: 99%

Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

View full text Add to dashboard Cite

Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the 6 perspective of EurOPDX, an international initiative devoted to PDX-based research.Response to anticancer therapies varies owing to the substantial molecular heterogeneity of human tumours and to poorly defined mechanisms of drug efficacy and resistance 1 . Immortalized cancer cell lines, either cultured in vitro or grown as xenografts, cannot interrogate the complexity of human tumours, and only provide determinate insights into human disease, as they are limited in number and diversity, and have been cultured on plastic over decades 2 .This disconnection in scale and biological accuracy contributes considerably to attrition in drug development [3][4][5] .Surgically derived clinical tumour samples that are implanted in mice (known as patient-derived xenografts (PDXs)) are expected to better inform therapeutic development strategies. As intact tissue -in which the tumour architecture and the relative proportion of cancer cells and stromal cells are both maintained -is directly implanted into recipient animals, the alignment with human disease is enhanced. More importantly, PDXs retain the idiosyncratic characteristics of different tumours from different patients; hence, they can effectively recapitulate the intra-tumour and inter-tumour heterogeneity that typifies human cancer 6-9 . 7 Exhaustive information on the key characteristics and the practical applications of PDXs can be found in recent reviews [10][11][12][13] . In this Opinion article, we discuss basic methodological concepts, as well as challenges and opportunities in developing "next-generation" models to improve the reach of PDXs as preclinical tools for in vivo studies (TABLE 1). We also elaborate on the merits of PDXs for exploring the intrinsic heterogeneity and subclonal genetic evolution of individual tumours, and discuss how this may influence therapeutic resistance. Finally, we examine the utility of PDXs in navigating complex variables in clinical decision-making, such as the discovery of predictive and prognostic biomarkers, and the categorization of genotype-drug response correlations in high-throughput formats. Being primarily co-authored by leading members of the EurOPDX Consortium (see Further information), we provide...

show abstract

mentioning

confidence: 99%

Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

View full text Add to dashboard Cite

show abstract

“…PDX maintain the genetic and histologic features of the original tumor (18,26,27). For instance, a good prediction of patient treatment efficacy using PDXs has been reported (28). Nevertheless, it is important to note that, even if PDXs are today recognized as a robust in vivo model for preclinical assays, the microenvironment remains of murine origin.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

Leconet

Chentouf

Manoir

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).Experimental Design: We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration, and invasion signaling pathways.Results: Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion. In vitro stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, and VIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6-dependent cell signaling implicated in EMT and in cell migration/invasion.Conclusions: The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation.

show abstract

“…39 PDXs provide an attractive model for personalized cancer therapy and have already shown promise in the treatment of sarcomas. 40 However, freshly isolated PPCLs will enable evaluation of the heterogeneity of cancer cell biology and the identification of more appropriate targets for therapeutic intervention. In addition, it will allow for the potential high-throughput pharmacologic screening of individualized therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Isolation of Pancreatic Cancer Cells from a Patient-Derived Xenograft Model Allows for Practical Expansion and Preserved Heterogeneity in Culture

Pham

Delitto

Knowlton

et al. 2016

The American Journal of Pathology

View full text Add to dashboard Cite

Patient‐derived xenografts for individualized care in advanced sarcoma

Cited by 150 publications

References 25 publications

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

Isolation of Pancreatic Cancer Cells from a Patient-Derived Xenograft Model Allows for Practical Expansion and Preserved Heterogeneity in Culture

Contact Info

Product

Resources

About