**6. Conclusions**

#### *6.1. Implications for Novel Mechanisms of Idiopathic Short Stature*

The novel association of IGFs with GRP94 that modulates production of IGFs has two implications for idiopathic short stature and other growth deficiencies. First, as allelic variations of the chaperone are likely to be new determinants of stature, there are now new target genes that can be screened to explain clinical observations. Second, based on other interacting proteins like ASNA1, we expect that the production of multiple insulin-related proteins will be sensitive to the activity of these proteins, in addition to the quality of the insulin-related protein itself. The chaperone machinery can be modulated with small molecules, so either GRP94 itself or its interacting proteins provide a novel way to manipulate both IGF deficiency and excessive production.

#### *6.2. Implications for Cancer Treatment*

The IGF-GRP94 interaction has similar implications for cancer, suggesting a potential role for both genetic screening for and pharmacological agents against the GRP94 machinery. Tumors often conscript IGF system overactivity as a means of furthering the neoplastic process. Autocrine/paracrine IGF overexpression by tumor cells or supporting stromal cells serves to stimulate cancer progression. As an obligate chaperone for secretion of both IGF-I and IGF-II, GRP94 may become a novel target for anti-neoplastic therapy. This may be particularly important for cancers like breast and prostate that become IGF-dependent when they become sex hormone-independent. It is conceivable that di fferences in the association of IGF-I and IGF-II with GRP94 can be exploited for selective tissue targeting of compounds and it is also possible that distinct, tissue-specific auxiliary proteins are involved in complex formation in di fferent cells and therefore can be targeted selectively.

**Funding:** This research was funded in part by NIH gran<sup>t</sup> AG-18001 (to Y.A. and A.G.) and by European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme (to M.T.M.).

**Conflicts of Interest:** A.G. and Y.A. declare that they have interest in intellectual property in growth control, held by CHOP, related to the subject of this work.
