Targeted morphoproteomic profiling of Ewing's sarcoma treated with insulin-like growth factor 1 receptor (IGF1R) inhibitors: response/resistance signatures.

Vivek Subbiah,Robert Benjamin,Aung Naing,Helen Chen,Razelle Kurzrock,Pete Anderson,Laurence Doyle,Robert E Brown,Patricia Lorusso,Benjamin Edward Rich

doi:10.1371/journal.pone.0018424

Abstract

BackgroundInsulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewing's sarcoma. We performed morphoproteomic profiling to better understand response/resistance mechanisms of Ewing's sarcoma to IGF1R inhibitor-based therapy.Methodology/Principal FindingsThis pilot study assessed two patients with advanced Ewing's sarcoma treated with IGF1R antibody alone followed by combined IGF1R inhibitor plus mammalian target of rapamycin (mTOR) inhibitor treatment once resistance to single-agent IGF1R inhibitor developed. Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor. The initial remarkable radiographic responses to IGF1R-antibody therapy was followed by resistance and then response to combined IGF1R plus mTOR inhibitor therapy in both patients, and then resistance to the combination regimen in one patient. In patient 1, upregulation of p-Akt and p-mTOR in the tumor that relapsed after initial response to IGF1R antibody might explain the resistance that developed, and the subsequent response to combined IGF1R plus mTOR inhibitor therapy. In patient 2, upregulation of mTOR was seen in the primary tumor, perhaps explaining the initial response to the IGF1R and mTOR inhibitor combination, while the resistant tumor that emerged showed activation of the ERK pathway as well.Conclusion/SignificanceMorphoproteomic analysis revealed that the mTOR pathway was activated in these two patients with advanced Ewing's sarcoma who showed response to combined IGF1R and mTOR inhibition, and the ERK pathway in the patient in whom resistance to this combination emerged. Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewing's sarcoma merits further investigation as a guide to understanding response and resistance signatures.

Highlights

Ewing’s sarcoma is the second most common malignant bone tumor in children, adolescents and young adults
Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewing’s sarcoma merits further investigation as a guide to understanding response and resistance signatures
Patient Selection, Treatment and Clinical Assessments We reviewed the medical records of two patients with Ewing’s sarcoma who were seen in the Phase I Clinical Trials Program at The University of Texas MD Anderson Cancer Center and initially treated with an Insulin-like growth factor 1 receptor (IGF1R) inhibitor alone, subsequently with an IGF1R and mammalian target of rapamycin (mTOR) inhibitor combination

Summary

Introduction

Ewing’s sarcoma is the second most common malignant bone tumor in children, adolescents and young adults. Despite using a multimodal approach combining surgery, chemotherapy, and radiation, a therapeutic plateau has been attained with no change in overall survival [1,2,3,4,5]. Survival remains poor for patients with metastatic disease. For metastatic Ewing’s sarcoma at diagnosis, the risk of refractory or recurrent disease approaches 80% after initial therapy and the outcome of recurrent disease is poor with event-free survival less than 20% [3]. Treatment options for patients with refractory or recurrent Ewing’s sarcoma are limited. Insulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewing’s sarcoma. We performed morphoproteomic profiling to better understand response/resistance mechanisms of Ewing’s sarcoma to IGF1R inhibitor-based therapy

Methods

Results

Conclusion