The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link

Abstract

Numerous epidemiological and pre-clinical studies have demonstrated that the insulin/insulin-like growth factor (IGF) system plays a key role in the development and progression of several types of cancer. Insulin/IGF signaling, in cooperation with chronic low-grade inflammation, is also an important contributor to the cancer-promoting effects of obesity. However, clinical trials for drugs targeting different components of this system have produced largely disappointing results, possibly due to the lack of predictive biomarker use and problems with the design of combination therapy regimens. With careful attention to the identification of likely patient responders and optimal drug combinations, the outcome of future trials may be improved. Given that insulin/IGF signaling is known to contribute to obesity-associated cancer, further investigation regarding the efficacy of drugs targeting this system and its downstream effectors in the obese patient population is warranted.

Keywords: biomarkers; energy balance; insulin; insulin-like growth factor; obesity.

Figure 1

Interactions between the key components of the insulin/IGF system. The receptors of the insulin/IGF system are tetramers comprised of two half receptors, each with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. IGF-IIR is the exception, as it lacks a kinase domain. Both IGF-IR and IR homodimers and IGF-IR/IR heterodimers can form, depending on the relative abundance of the half receptors. Alternative splicing also results in two different forms of the IR half receptor, IR-A and IR-B. The ligands of this system (insulin, IGF-I, and IGF-II) vary in their affinity for the different receptors. IGF-I primarily binds to homo or heterodimers containing an IGF-IR half receptor, while insulin has the greatest affinity for IR-A and IR-B. In contrast, IGF-II binds IR-A with high affinity and can also bind IGF-IR homo or heterodimers, but binding to IGF-IIR limits its bioavailability. Similarly, the IGFBPs sequester both the IGFs, preventing their ability to bind and activate their cognate receptors. The signaling pathways downstream of the activated IR-A and IGF-IR homodimers are known to stimulate cancer cell proliferation, survival, migration, and invasion, while IR-B is more closely linked to metabolic regulation. The exact functions of the various heteroreceptor combinations have not been clearly defined, but it is likely that receptors containing an IR-A or IGF-IR holoreceptor will modulate cancer growth and metastasis to some degree.

Figure 2

Cellular signaling pathways downstream of the insulin/IGF receptors. Insulin and IGF activate two major signaling pathways, Akt and Ras-MAPK. Stimulation of Akt activates the mTOR signaling complex, leading to greater protein translation. In addition, Akt and Ras-MAPK enhance cellular proliferation, survival, angiogenesis, and invasion via regulation of gene transcription.

Figure 3

Mechanisms of insulin/IGF system-targeting drugs. The three types of insulin/IGF system-targeting drugs are illustrated. IGF-IR monoclonal antibodies bind IGF-IR, leading to its internalization and degradation. IGF-IR/IR TKI drugs decrease receptor activity by competing for the ATP binding site on the receptor’s kinase domain, blocking transduction of a signal to downstream effectors. Finally, IGF monoclonal antibodies directly bind both IGF-I and IGF-II, preventing them from binding and activating the system’s receptors. Drug-induced decreases in IGF-IR signaling disrupt the pituitary-mediated negative feedback loop regulating IGF-I production, leading to higher IGF-I levels and, indirectly, greater insulin levels.

Figure 4

Targeting insulin/IGF signaling may attenuate the pro-tumor effects of obesity. Obesity is associated with higher insulin and bioavailable IGF-I levels which, in cooperation with chronic inflammation, contributes to greater risk and progression of many cancers. The pro-tumor effects of obesity can be mitigated directly by obesity reversal using calorie restriction and increased physical activity. Pharmaceutical interventions targeting obesity-associated insulin/IGF and inflammatory signaling or their downstream effectors may also improve patient risk and outcome.