TY - JOUR
T1 - Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment
AU - Garralda, Elena
AU - Paz, Keren
AU - López-Casas, Pedro P.
AU - Jones, Siân
AU - Katz, Amanda
AU - Kann, Lisa M.
AU - López-Rios, Fernando
AU - Sarno, Francesca
AU - Al-Shahrour, Fátima
AU - Vasquez, David
AU - Bruckheimer, Elizabeth
AU - Angiuoli, Samuel V.
AU - Calles, Antonio
AU - Diaz, Luis A.
AU - Velculescu, Victor E.
AU - Valencia, Alfonso
AU - Sidransky, David
AU - Hidalgo, Manuel
PY - 2014/5/1
Y1 - 2014/5/1
N2 - Background: Current technology permits anunbiasedmassive analysis of somatic genetic alterations from tumorDNA aswell as the generation of individualizedmouse xenografts (Avatarmodels). Thiswork 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.
AB - Background: Current technology permits anunbiasedmassive analysis of somatic genetic alterations from tumorDNA aswell as the generation of individualizedmouse xenografts (Avatarmodels). Thiswork 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.
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U2 - 10.1158/1078-0432.CCR-13-3047
DO - 10.1158/1078-0432.CCR-13-3047
M3 - Article
C2 - 24634382
AN - SCOPUS:84899707234
SN - 1078-0432
VL - 20
SP - 2476
EP - 2484
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -