ROLE OF IGF SIGNALING UPON EWINGS SARCOMA PATIENT

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DESCRIPTION: The Ewing's sarcoma family of tumors (ESFT) affects patients between the ages of 3 and 40 years, with most cases occurring in the second decade of life. Patients who present with localized tumors have approximately 70 percent disease-free survival, while those who present with metastatic ESFT have a poor prognosis despite high dose chemotherapy. Two challenges arise. The first is to stratify patients with localized or metastatic tumors into those who will survive with current therapies and those who will require more intensive therapy. The second is to develop novel strategies for treating those ESFT patients who are not currently surviving despite intensive therapies such as bone marrow transplantation. The insulin-like growth factor type 1 (IGF-I) and its receptor (IGF-IR) are known to play a significant role in ESFT growth and transformation. The applicant's recent work shows that IGF-I signaling participates in ESFT chemoresistance. ESFT contain a tumor specific translocation, t(11;22), with various exonal combinatorial possibilities between individual tumors. One of these translocation types, type l, has been associated with increased survival of patients with localized disease and with decreased expression of the IGF-IR. Therefore, the applicant hypothesizes that increased IGF signaling in patients with ESFT predicts for decreased survival. Understanding altered IGF signaling could thus provide patient stratification and therapeutic targets. In order to define the relevance of IGF signaling in ESFT patients, the components of the IGF signaling system need to be analyzed. This proposal seeks to understand if quantitative changes in ligand, binding proteins, or receptor predict clinical course by utilizing a prospective clinical trial. The applicant proposes three aims: (1) To measure the IGF-I and IGFBP-3 serum levels in all patients enrolled in the upcoming localized and metastatic ESFT protocols. Serum IGF-I, IGFBP-3 and IGFBP-3:IGF-I will be analyzed to identify if these indices predict differences in clinical presentation chemo-responsiveness and event-free survival, (2) To measure the IGF-IR levels in ESFT tumors at the time of diagnosis from all patients enrolled in both the localized and metastatic ESFT protocols and correlate IGF-IR number and tumor IGF-I levels with clinical presentation, response to chemotherapy, and prognosis, and (3) To correlate the findings with the ESFT translocation types. The strengths of this proposal are that the proposed pediatric clinical trials offer an opportunity to compare similarly treated patients for effects of IGF signaling components. The applicant's findings could be utilized for future patient stratification, and the methods developed here can be applied to any malignancy in which IGF signaling may play a key role, including breast, prostate, and colon. This application proposes to measure IGF-I, IGFBP-3, and IGF-IR levels in all patients enrolled in upcoming clinical trials for Ewing's sarcoma family of tumors [ESFT] conducted by the Children's Cancer Group/Pediatric Oncology Group, evaluate correlation of indices with response to therapy and survival, and correlated findings with ESFT translocation subtypes.