Abstract 1948: Tumor-specific copy number alterations uncover therapeutic opportunities in osteosarcoma
Authors: Sayles Leanne C. , Breese Marcus , Koehne Amanda L. , Leung Stanley , Spillinger Aviv , Lee Alex , Shah Avanthi , Straessler Krystal , Spunt Sheri , Marina Neyssa , Jacobson Damon , Avedian Raffi S. , Mohler David G. , DuBois Steven , Hawkins Douglas S. , Sweet-Cordero E. Alejandro 
Published: July 2017

Osteosarcoma (OS) is a highly malignant cancer for which no targeted therapies are currently available. Current treatment modalities are limited to intensive, highly toxic chemotherapy and surgical resection. OS is characterized by wide spread copy number alterations and structural rearrangements. In contrast, no recurrent point mutations in protein-coding genes have been identified, suggesting that copy number alterations (CNAs) are key oncogenic drivers in this disease. However, as copy number alterations are highly heterogeneous, it is likely that each tumor has a distinct set of oncogenic drivers, making a unified treatment approach difficult to define. To identify candidate patient-specific drivers, we used a simple heuristic based on degree of amplification (as assessed by Whole Genome Sequencing) and changes in gene expression (as assessed by RNA sequencing). Using patient-derived tumor xenografts (PDTXs), we assessed if individual OS tumors respond to targeted therapy selected based on this approach. We rank-ordered CNAs in 9 PDTXs by the amplitude of the copy number gain and identified 5 pathways for targeted therapy including CCNE1, MYC, CDK4, PTEN/AKT and AURKB. Next, we prioritized drug choices to those that are in clinical trials and that are readily available and identified 5 drug matches for 9 PDTXs. We used the CDK2 inhibitor Dinaciclib for CCNE1 amplification and observed TGI of 85.5% and 67.8% for 2 different CCNE1 amplified PDTXs tested. CDK9 inhibitor AT7519 was used to treat 2 different MYC amplified PDTXs resulting in TGI of 104% and 83.9%. CDK4 amplified PDTXs were treated with CDK4/6 inhibitor, Palbociclib, resulting in TGI of 82.7%. AKT1 inhibitor MK-2206 was used to treat either AKT1 gains or PTEN loss resulting in TGI of 65.6% and 60.8% respectively. AURKB inhibitor AZD-1152 for AURKB amplified PDTXs in combination with cisplatin resulting in TGI 85.8%. These results support the hypothesis that specific genes within CNA regions serve as oncogenic drivers and that these represent therapeutic opportunities in OS. Our studies provide a roadmap for personalized genome-informed therapy of osteosarcoma, a cancer in which no new therapies have been identified in over 30 years.

Citation Format: Leanne C. Sayles, Marcus Breese, Amanda L. Koehne, Stanley Leung, Aviv Spillinger, Alex Lee, Avanthi Shah, Krystal Straessler, Sheri Spunt, Neyssa Marina, Damon Jacobson, Raffi S. Avedian, David G. Mohler, Steven DuBois, Douglas S. Hawkins, E. Alejandro Sweet-Cordero. Tumor-specific copy number alterations uncover therapeutic opportunities in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1948. doi:10.1158/1538-7445.AM2017-1948