Customizing the Targeting of IGF-1 Receptor

Renato Baserga

Disclosures

Future Oncol. 2009;5(1):43-50. 

In This Article

What Can We Learn from Ewing's Sarcoma?

There are several reports from meetings that Ewing's sarcomas in human patients are exquisitely sensitive to antibodies to the IGF-IR. Experimental data has given ample evidence that targeting of the IGF-IR was effective in these tumors. The high sensitivity of human Ewing's sarcomas to IGF-IR targeting raises some interesting questions. One obvious question is: why are they so sensitive?

The review by Scotlandi and Picci[45] provides some answers to the question. In Ewing's sarcoma, the IGF-IR is constitutively activated by autocrine production of IGF-1. This is confirmed by the observation that EWS-FLI1, the genetic hallmark of Ewing's sarcoma, is transforming only in the presence of the IGF-IR and produces a robust upregulation of IGF-1. It is intriguing that the Ewing's sarcoma oncogene interacts directly with IRS-1.[23] This seems to be another example of a tumor with an acquired taste for growth in IGF-1, a tumor, so to speak, trained to grow in IGF-1. However, this raises another question. If Ewing's sarcomas are so sensitive to IGF-IR targeting, why is it that the tumor cannot adapt or switch to another growth factor when the receptor is downregulated by treatment? Are IGFs obligatory for Ewing's sarcoma? Is the interaction between IRS-1 and the oncogene the reason for this strict dependence? The last possibility is attractive. The IRS-1/oncogene interaction is reminiscent of the Byron et al.[5] experiment, with an activated IRS-1 promoting the dependence of the cells on IGF-1 stimulation. It is also compatible with the observation of Sun and Baserga[28] that when IRS-1 is directly activated by v-src, the IGF-IR is no longer needed for transformation. This is an exquisite basic science problem, but it may hold the secret to successful treatment of tumors with IGF-IR antibodies.

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