Of Mice and Melanoma: PDX System for Modeling Personalized Medicine

Hartsough, Edward J.; Aplin, Andrew E.

doi:10.1158/1078-0432.ccr-15-3054

Cited by 6 publications

(6 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the use of PDXs in routine diagnostic may not be a realistic goal due to variability in engraftment, latency period, number of animals required and costs [14], they may provide an unlimited resource of tumor cells for both small-scale as well as large-scale ex vivo drug screening. Here we demonstrated that PDXs assessed for treatment responses using the ex vivo assay show a high degree of concordance with results observed when analyzing the corresponding patient tumors directly, or when treating PDXs in vivo, supporting previous observations that early PDX passages resemble the original tumor [59]. In agreement with our findings, short-time ex vivo cultures of breast cancer PDXs were recently found to predict in vivo drug responses [60].…”

Section: Discussionsupporting

confidence: 90%

A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases

Flørenes

Flem-Karlsen

McFadden

et al. 2019

Translational Oncology

View full text Add to dashboard Cite

Although clinical management of melanoma has changed considerably in recent years, intrinsic treatment resistance remains a severe problem and strategies to design personal treatment regimens are highly warranted. We have applied a three-dimensional (3D) ex vivo drug efficacy assay, exposing disaggregated cells from 38 freshly harvested melanoma lymph node metastases and 21 patient derived xenografts (PDXs) to clinical relevant drugs for 7 days, and examined its potential to evaluate therapy response. A strong association between Vemurafenib response and BRAF mutation status was achieved ( P < .0001), while enhanced viability was seen in some NRAS mutated tumors. BRAF and NRAS mutated tumors responded comparably to the MEK inhibitor Cobimetinib. Based on the ex vivo results, two tumors diagnosed as BRAF wild-type by routine pathology examinations had to be re-evaluated; one was subsequently found to have a complex V600E mutation, the other a double BRAF mutation (V600E/K601 N). No BRAF inhibitor resistance mechanisms were identified, but PIK3CA and NF1 mutations were identified in two highly responsive tumors. Concordance between ex vivo drug responses using tissue from PDXs and corresponding patient tumors demonstrate that PDX models represent an indefinite source of tumor material that may allow ex vivo evaluation of numerous drugs and combinations, as well as studies of underlying molecular mechanisms. In conclusion, we have established a rapid and low cost ex vivo drug efficacy assay applicable on tumor tissue from patient biopsies. The 3D/spheroid format, limiting the influence from normal adjacent cells and allowing assessment of drug sensitivity to numerous drugs in one week, confirms its potential as a supplement to guide clinical decision, in particular in identifying non-responding patients.

show abstract

Section: Discussionsupporting

confidence: 90%

A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases

Flørenes

Flem-Karlsen

McFadden

et al. 2019

Translational Oncology

View full text Add to dashboard Cite

show abstract

“…Spontaneous melanoma is very rare in mouse, but the model is notably used as a support for patient-derived xenografts (PDXs) in immunocompromised animals. PDX mice properly model the human disease and can guide personalized therapy decisions ( Hartsough and Aplin, 2016 ). Another essential application of mouse as a model is the relatively easy manipulation of its genome.…”

Section: Animal Models Of Melanomamentioning

confidence: 99%

The MeLiM Minipig: An Original Spontaneous Model to Explore Cutaneous Melanoma Genetic Basis

Bourneuf

2017

Front. Genet.

View full text Add to dashboard Cite

Melanoma is the deadliest skin cancer and is a major public health concern with a growing incidence worldwide. As for other complex diseases, animal models are needed in order to better understand the mechanisms leading to pathology, identify potential biomarkers to be used in the clinics, and eventually molecular targets for therapeutic solutions. Cutaneous melanoma, arising from skin melanocytes, is mainly caused by environmental factors such as UV radiation; however a significant genetic component participates in the etiology of the disease. The pig is a recognized model for spontaneous development of melanoma with features similar to the human ones, followed by a complete regression and a vitiligo-like depigmentation. Three different pig models (MeLiM, Sinclair, and MMS-Troll) have been maintained through the last decades, and different genetic studies have evidenced a complex inheritance of the disease. As in humans, pigmentation seems to play a prominent role, notably through MC1R and MITF signaling. Conversely, cell cycle genes as CDKN2A and CDK4 have been excluded as predisposing for melanoma in MeLiM. So far, only sparse studies have focused on somatic changes occurring during oncogenesis, and have revealed major cytological changes and a potential dysfunction of the telomere maintenance system. Finally, the spontaneous tumor progression and regression occurring in these models could shed light on the interplay between endogenous retroviruses, melanomagenesis, and adaptive immune response.

show abstract

“…Mouse models applied for melanoma study have a long history [ 77 ] and exhibit several advantages compared to other animal models (fish, opossum, horse, dogs, pigs), such as: relevant known data concerning the genetic background which allows the possibility of genetic manipulation, easy breeding and handling, multiple studies about molecular pathways dissection, and representing appropriate hosts for patient-derived xenografts (PDXs) to develop semblable human disease and to establish personalized antimelanoma therapies [ 21 , 78 ].…”

Section: Murine Models Of Melanomamentioning

confidence: 99%

Cutaneous Melanoma—A Long Road from Experimental Models to Clinical Outcome: A Review

Coricovac

Dehelean

Moacă

et al. 2018

IJMS

View full text Add to dashboard Cite

Cutaneous melanoma is a complex disorder characterized by an elevated degree of heterogeneity, features that place it among the most aggressive types of cancer. Although significant progress was recorded in both the understanding of melanoma biology and genetics, and in therapeutic approaches, this malignancy still represents a major problem worldwide due to its high incidence and the lack of a curative treatment for advanced stages. This review offers a survey of the most recent information available regarding the melanoma epidemiology, etiology, and genetic profile. Also discussed was the topic of cutaneous melanoma murine models outlining the role of these models in understanding the molecular pathways involved in melanoma initiation, progression, and metastasis.

show abstract

Of Mice and Melanoma: PDX System for Modeling Personalized Medicine

Cited by 6 publications

References 13 publications

A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases

A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases

The MeLiM Minipig: An Original Spontaneous Model to Explore Cutaneous Melanoma Genetic Basis

Cutaneous Melanoma—A Long Road from Experimental Models to Clinical Outcome: A Review

Contact Info

Product

Resources

About