2008 AACR meeting, evidence of activation of IGF1R in ASPS

[Olga]

"ASPS ... exhibited a state of chronic IGF1R activation...
We show evidence of activation of IGF1R in clinical specimens of ASPS'



2008 AACR Annual Meeting
April 12-16, 2008
San Diego, CA
Abstract Number: 2192
Session Title: Molecular Correlates 2
Presentation Title:

Activation index of IGF-IR in sarcoma subtypes
Presentation Start/End Time:

Monday, Apr 14, 2008, 8:00 AM -12:00 PM
Location:

Exhibit Hall B-F, San Diego Convention Center
Poster Section:

25
Poster Board Number:

7
Author Block:

Carolyn J. Hoban, Daffyd Thomas, Dina Lev, R. Pollock, Laurence H. Baker. University of Michigan, Ann Arbor, MI, MD Anderson Cancer Center, Houston, TX
Objectives. IGF-1R expression is important for cell growth, proliferation, survival and progression of cancer. Expression of IGF1R and its ligands have been demonstrated in sarcoma subtypes, such as rhabdomyosarcoma, osteosarcoma, small blue cell sarcomas and synovial sarcoma. With the current clinical development of candidate drugs that target the IGF1 axis, the role of IGF1R in sarcoma subtypes is a major focus of research. We examined histological subtypes of sarcomas and compared IGF1R activation status in sarcoma subtypes. We undertook this study to determine the level and activation status of IGF1R pathway in clinical specimens of sarcoma subtypes in order to develop markers predictive of response or resistance to IGF1R therapies in future clinical studies.
Methods. Frozen human sarcomas were obtained and protein was extracted with protease and phosphatase inhibitors. Total and phospho-IGF1R levels were determined using capture ELISA and confirmed by immunoblot. The activation index (amount of phosphorylated to total IGF1R) was determined for each clinical specimen. Western blot analysis of effectors downstream of IGF1R was performed. Sarcoma subtypes were confirmed in clinical specimens by molecular diagnostic assays.
Results Among the sarcoma subtypes assayed, Ewing’s sarcoma family of tumors (EWS), alveolar soft part sarcoma (ASPS), malignant peripheral nerve sheath tumor (MPNST), synovial sarcoma (SS), osteosarcoma (OS), myxoid liposarcoma (MLPS), leiomyosarcoma (LMS) and malignant fibrous histiocytoma (MFH), there was significant heterogeneity of IGF1R expression. The highest levels of IGF1R were found in MPNST, OS and MLPS. However, LMS, ASPS, and OS had lower levels of phospho-IGF1R than MPNST, synovial sarcoma, MLPS, and EWS. While OS tumors expressed high levels of IGF1R, the fraction of activated phospho-IGF1R was low. In contrast, MPNST, ASPS and EWS exhibited a state of chronic IGF1R activation. The activation index of IGF1R is highest in EWS. Ewing’s sarcoma clinical specimens with the highest levels of IGF1R activation were also associated with activation of the mTOR/S6K1 axis.
Conclusion. These results demonstrated the heterogeneity of IGF1R levels and activation of signal transduction pathways among sarcoma subtypes. We show evidence of activation of IGF1R in clinical specimens of EWS, ASPS and MPNST sarcoma subtypes. The activation index, along with IGF1 ligands and binding proteins, will be incorporated into translational science of future clinical studies using combinations of drugs that target IGF1R and mTOR axis.

I think it will justify the inclusion of the ASPS patients into the IGF1 clinical trials.