Integrated Next-Generation Sequencing and Avatar Mouse Models for Personalized Cancer Treatment

Abstract

Background Current technology permits an unbiased massive analysis of somatic genetic alterations from tumor DNA as well as the generation of individualized mouse xenografts (Avatar models). This work aimed to evaluate our experience integrating these two strategies to personalize the treatment of patients with cancer. Methods We performed whole-exome sequencing analysis of 25 patients with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. Avatar models were used as an in vivo platform to test proposed treatment strategies. Results Successful exome sequencing analyses have been obtained for 23 patients. Tumor-specific mutations and copy-number variations were identified. All samples profiled contained relevant genomic alterations. Tumor was implanted to create an Avatar model from 14 patients and 10 succeeded. Occasionally, actionable alterations such as mutations in NF1, PI3KA, and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and, accordingly, treatment of the patients with these drugs was not effective. To date, 13 patients have received a personalized treatment and 6 achieved durable partial remissions. Prior testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in some patients with no actionable mutations. Conclusion The use of full genomic analysis for cancer care is encouraging but presents important challenges that will need to be solved for broad clinical application. Avatar models are a promising investigational platform for therapeutic decision making. While limitations still exist, this strategy should be further tested.

The Spectrum of Clinical Utilities in Molecular Pathology Testing Procedures for Inherited Conditions and Cancer

“…In patients who have failed traditional therapy, the finding of an actionable mutation on an NGS panel has been associated, in some cases, with dramatic responses [48][49][50][51][52][53][54] . The merit of such off-label use is evaluated at present on a case-by-case basis.…”

Development of bioluminescent chick chorioallantoic membrane (CAM) models from primary pancreatic cancer cells: A platform for drug testing

“…Despite the advances in molecular biology, in technological applications for genetically engineered mouse models (GEMMs), and the intense focus on the identification of prognostic and predictive biomarkers in "avatar" mice 22 , developments in the area of anticancer drug testing in animal models remain limited. With this study, we propose the repositioning in pancreatic preclinical research of the CAM in vivo model, already established for the study of angiogenesis.…”

“…This might be at least partially explained by two recent studies revealing that depletion of stromal cells can prompt a more biologically aggressive form of PDAC with poorly differentiated histology, increased vascularity and proliferation, while depletion of carcinoma-associated fibroblasts induces immunosuppression, associated to epithelial-to-mesenchymal transition [23][24][25] . Most recently, Hidalgo and collaborators used "avatar" models as an in vivo platform to test treatment strategies suggested by parallel whole-exome sequencing analysis of 25 patients with advanced solid tumors, including seven PDAC patients 22 . However, the use of primary xenografts has still several inherent limitations and deficiencies 26 .…”

De l’exome à l’avatar : vers une « oncologie de précision » ?

“…Une publication toute récente, émanant des mêmes équipes (en majorité espagnoles), présente les premiers résultats d'une approche associant séquençage et création d'un avatar [8]. Elle a porté sur 25 patients atteints de divers cancers à un stade avancé.…”

“…Par ailleurs, l'expérience à ce jour indique que le taux de succès est faible, seuls 10 à 20 % des interventions suggérées par la génomique s'avérant efficaces [2,3]. Il devient donc très important d'avoir des indications complémentaires pour faire le meilleur choix, et le passage par un test sur un avatar portant la tumeur du patient est indubitablement une option intéressante, d'autant que les études rapportées dans cette chronique montrent toutes une bonne cohérence entre efficacité sur l'avatar et réponse chez le patient [5][6][7][8]. Cette approche n'est pas parfaite : elle est coûteuse, techniquement exigeante et surtout elle impose un délai important (six mois environ) dans des situations où il est souvent urgent de trouver le bon traitement.…”