Melanoma patient-derived xenografts accurately model the disease and develop fast enough to guide treatment decisions

Abstract

The development of novel therapies against melanoma would benefit from individualized tumor models to ensure the rapid and accurate identification of biomarkers of therapy response. Previous studies have suggested that patient-derived xenografts (PDXes) could be useful. However, the utility of PDXes in guiding real-time treatment decisions has only been reported in anecdotal forms. Here tumor biopsies from patients with stage III and IV metastatic malignant melanoma were transplanted into immunocompromised mice to generate PDXes. 23/26 melanoma biopsies generated serially transplantable PDX models, and their histology, mutation status and expression profile resembled their corresponding patient biopsy. The potential treatment for one patient was revealed by an in vitro drug screen and treating PDXes with the MEK inhibitor trametinib. In another patient, the BRAF mutation predicted the response of both the patient and its corresponding PDXes to MAPK-targeted therapy. Importantly, in this unselected group of patients, the time from biopsy for generation of PDXes until death was significantly longer than the time required to reach the treatment phase of the PDXes. Thus, it could be clinically meaningful to use this type of platform for melanoma patients as a pre-selection tool in clinical trials.

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma

“…Support for the predictive power of PDXs has been shown in a small number of clinical cases (22,46,47), although limitations of PDX models due to tumor heterogeneity and interspecies compatibility have also been noted (48,49). Critically, our PDX models were established with a median latency of 49 days, and we show that this provided sufficient time to test clinically relevant questions for numerous patients in this study.…”

“…Serial analysis of ctDNA can be used to track genomic evolution of metastatic cancers in response to therapy to complement invasive biopsy approaches and identify mutations associated with acquired drug resistance in advanced cancers ( 21 ), but it is unclear how this technology can be used in the routine setting of a hospital. Patientderived xenografts (PDX) also have the potential to assist personalized medicine decisions ( 22 ), but their development requires access to tumor tissue that is often inaccessible or…”

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

“…The much higher success rate of PDX irrespective of mutational subgroup make PDX more clinically relevant (Byrne et al, 2017; Townsend et al, 2016). Several other research groups have established melanoma PDX models (Einarsdottir et al, 2014; Gao et al, 2015; Girotti et al, 2016; Kemper et al, 2016; Quintana et al, 2012). Quintana et al established PDX from 25 stage IIIB/C patients and correlated spontaneous metastasis in the animals with patient outcome.…”

“…Melanoma is uniquely suited to this approach as even single cells are tumorigenic in vivo (Quintana et al, 2008). Melanoma PDX were shown to accurately model the clinical disease and response to targeted therapy (Einarsdottir et al, 2014). We have shown recently that PDX derived from BRAF inhibitor relapsed patients and expanded on chronic therapy could be used to identify effective second line combination therapies based on genomic and proteomic profiling (Krepler et al, 2016).…”

BRAFV600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

“…All animal experiments were performed in accordance with European Union directive 2010/63 (Regional Animal Ethics Committee of Gothenburg approval 287/289-12 and 36-2014). Establishment of PDXs was performed as previously described (18). For the establishment of the CDXs, MML-1 cells were suspended in culture media and mixed 1:1 with Matrigel (BD Bioscience), and 2 × 10 5 cells were transplanted s.c. into the flank of NOD-SCID IL2Rc null (NOG) mice.…”