A tale of two receptors: insulin and insulin-like growth factor signaling in cancer

Abstract

Inhibition of the type I IGF receptor (IGF1R) has been the focus of numerous clinical trials. Two reports in this issue describe the results of phase I trials of an IGF1R tyrosine kinase inhibitor OSI-906. This commentary will describe the complex endocrine changes induced by these types of agents.

Figure 1

Coordination of IGF-I and insulin signaling. A, In normal conditions, the hypothalamus produces Growth Hormone Releasing Hormone (GHRH) and Somatostatin to regulate Growth Hormone production by the pituitary. Growth Hormone interacts with Growth Hormone receptor in the liver resulting in increased serum levels of IGF-I. IGF-I stimulates growth in normal cells by stimulating IGF1R, but also regulates cancer cell growth, survival and metastasis. Insulin produced by the pancreas interacts with several tissues to maintain glucose homeostatsis including the liver. While most cancer cells also express insulin receptor and under normal physiologic conditions, insulin levels are low (dotted lines) except in response to a meal. IGF-II is produced from many different tissues and binds both receptors. B, When IGF1R signaling is disrupted by a monoclonal antibody (red symbol), negative endocrine Growth Hormone feedback is disrupted as the brain does not sense IGF-I levels. Elevated Growth Hormone (orange arrow) levels result in insulin resistance (partially due to increased free fatty acid efflux from the liver) in peripheral tissues resulting in enhanced insulin production by the pancreas (thick lines, orange arrow). These elevated insulin levels may stimulate tumor growth. OSI-906 is not specific for insulin or IGF signaling and may be a more effective drug to block both IGF-I, IGF-II, and insulin signaling than IGF1R monoclonal antibodies.

Figure 1

Coordination of IGF-I and insulin signaling. A, In normal conditions, the hypothalamus produces Growth Hormone Releasing Hormone (GHRH) and Somatostatin to regulate Growth Hormone production by the pituitary. Growth Hormone interacts with Growth Hormone receptor in the liver resulting in increased serum levels of IGF-I. IGF-I stimulates growth in normal cells by stimulating IGF1R, but also regulates cancer cell growth, survival and metastasis. Insulin produced by the pancreas interacts with several tissues to maintain glucose homeostatsis including the liver. While most cancer cells also express insulin receptor and under normal physiologic conditions, insulin levels are low (dotted lines) except in response to a meal. IGF-II is produced from many different tissues and binds both receptors. B, When IGF1R signaling is disrupted by a monoclonal antibody (red symbol), negative endocrine Growth Hormone feedback is disrupted as the brain does not sense IGF-I levels. Elevated Growth Hormone (orange arrow) levels result in insulin resistance (partially due to increased free fatty acid efflux from the liver) in peripheral tissues resulting in enhanced insulin production by the pancreas (thick lines, orange arrow). These elevated insulin levels may stimulate tumor growth. OSI-906 is not specific for insulin or IGF signaling and may be a more effective drug to block both IGF-I, IGF-II, and insulin signaling than IGF1R monoclonal antibodies.