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

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

1. Elena Garralda1, 
2. Keren Paz2, 
3. Pedro P. López-Casas1, 
4. Sian Jones3,
5. Amanda Katz4, 
6. Lisa M. Kann5, 
7. Fernando López-Ríos6, 
8. Francesca Sarno7,
9. Fátima Al-Shahrour1, 
10. David Vasquez4, 
11. Elizabeth Bruckheimer8,
12. Samuel V. Angiuoli5, 
13. Antonio Calles9, 
14. Luis A. Diaz10, 
15. Victor E Velculescu11,
16. Alfonso Valencia12, 
17. David Sidransky13, and 
18. Manuel Hidalgo14,*

+Author Affiliations

1. ¹Clinical Research Programme, Spanish National Cancer Research Centre (CNIO)
2. ²Personalized Oncology, Champions Oncology
3. ³The Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins Kimmel Cancer Center
4. ⁴Champions Oncology, Champions Oncology
5. ⁵Science and Technology Park at Johns Hopkins, Personal Genome Diagnostics, Inc.
6. ⁶Gastointestinal Tumors, Therapeutics targets Laboratory
7. ⁷CIOCC, Centro Integral Oncologico Clara Campal (CIOCC)
8. ⁸Preclinical Development, Champions Biotechnology
9. ⁹Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute
10. ¹⁰1650 Orleans Street, Johns Hopkins
11. ¹¹Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
12. ¹²Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO)
13. ¹³Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins University
14. ¹⁴Clinical Research Program, Spanish National Cancer Research Center

1. ↵* Corresponding Author:
   Manuel Hidalgo, Clinical Research Program, Spanish National Cancer Research Center, Melchor Fernandez Almagro 3, Madrid, Madrid, 28029, Spain mhidalgo@cnio.es

Abstract

Background: Current technology permits an unbiased massive analysis of so-matic genetic alterations from tumor DNA as well as the generation of individu-alized mouse xenografts (Avatar models). This work aimed to evaluate our ex-perience integrating these two strategies to personalize the treatment of cancer patients. 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 has 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. In occasions 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 promising 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.

• Received November 5, 2013.
• Revision received February 9, 2014.
• Accepted February 10, 2014.

• Copyright © 2014, American Association for Cancer Research.