Abstract IA33: Combination targeted therapy in pediatric sarcomas

Abstract

Abstract Our group, and many others have documented a crucial role for IGFIR signaling in several pediatric sarcomas. These studies, along with the development of fully human IGFIR antibodies led to clinical testing of these blocking antibodies in rhabdomyosarcoma, Ewing's sarcoma, and osteosarcoma, along with a variety of other sarcomas. In general these single agent Phase 2 studies showed objective responses rates below 20%. Furthermore, even in responding patients, the duration of response is short-lived, typically less than 18 weeks. Thus the majority of patients do not have long term benefit from IGFIR blockade, indicating the presence of innate or acquired resistance to this therapeutic approach. We have been using xenografts of human rhabdomyosarcoma cell lines RD(embryonal) and RH30 (alveolar) to model both innate and acquired resistance to IGFIR blockade. Our xenograft models of rhabdomyosarcoma predicted short duration responses that mimicked the clinical observations, and we have been attempting to use these models to better understand how various signaling pathways in addition to IGFIR may interact and indeed be used as “by-pass” resistance pathways. Our hope is that this knowledge will lead to rational combination targeted therapy that we assume will be necessary for maximal clinical benefit. I will discuss one example of an additional signaling pathway that was activated upon IGFIR blockade, and how this information led to combination targeted therapy that holds therapeutic promise. We recently demonstrated that Src-Family Kinase (SFK) YES is highly expressed and functional in rhabdomyosarcomas. Since SFK signaling has been previously linked to IGF signaling in other tumor types, we evaluated the effect of IGFIR on YES activation. YES is rapidly activated upon IGFIR blockade using either a monoclonal antibody directed against the IGFIR or an IGFIR kinase inhibitor, suggesting that YES activation could play a role in resistance to IGFIR blockade. We next tested dual SFK and IGFIR inhibition and found that combined SFK and IGFIR inhibition led to more potent inhibition of both RD and RH30 rhabdomyosarcoma cell lines and perhaps most importantly led to increased apoptosis. Based on these promising in vitro effects, we evaluated the combination of IGFIR Ab, R1507 plus the SFK inhibitor, dasatinib, in our RD and RH30 xenografts. While both R1507 and dasatinib led to tumor growth inhibition as single agents, mice developed resistance to both single agents within 70-90 days of treatment. In contrast, the mice treated with the combination of R1507 and dasatinib did not develop resistance after 90 days and also showed enhanced tumor growth inhibition. This example highlights the need to better understand how signaling pathways interact so that one may predict consequences of therapeutic intervention using targeted agents and develop combinations that will undoubtedly be necessary to achieve the maximal clinical benefit of agents designed to inhibit specific signaling pathways. Citation Format: Lee J. Helman, Fernanda Arnaldez, Christine Heske, Xiaolin Wan, Choh Yeung. Combination targeted therapy in pediatric sarcomas. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA33.