http://www.ncbi.nlm.nih.gov/books/bv....chapter.53172 (many pages)
Conclusion
The IGF-IR is a promising target in breast cancer therapy because it signals to multiple pathways required for maintenance of the malignant phenotype. Given the role for IGF-IR in cell survival, it is logical to combine anti-IGF therapies with conventional agents. Indeed, the preclinical
data suggest that blockade of IGF-IR induces apoptosis and lowering a “survival threshold” with disruption of this signaling system should enhance chemotherapy efficacy.
However, there are several challenges that will need to be addressed before the idea that combination anti-IGF therapy and chemotherapy display synergy. First, there are many ways that IGF signaling could be targeted. As recently noted by Professor Baserga,
105 the potential anti-IGF strategies have gone from “rags to riches” in the course of a few short years. Clinical trials to test the most effective strategy will need to be completed before combination trials can begin. Second, the phenotypes regulated by IGF-IR are not restricted to survival alone. Since proliferation is also affected by IGF-IR, it will be important to consider scheduling and choice of chemotherapeutic agent when designing appropriate combinations. For example,
it is possible that anti-metabolites would be less efficacious when combined with anti-IGF because of the requirement for cells in S-phase for anti-metabolites to function. Indeed, interference between hormonal therapy and chemotherapy has been noted in breast cancer
106 and it is possible that such interference could exist between anti-IGF therapy and certain drugs. On the other hand,
agents that have a different mechanism of action, such as DNA alkylators or therapies that induce DNA strand breaks, may be enhanced by blocking IGF-IR due to the receptor's role in DNA repair. Careful preclinical studies will need to be performed before clinical trials should proceed with testing anti-IGF therapy with conventional cytotoxics. Lastly, the idea that multiple molecules are involved in growth factor signaling leads to the potential for “combination targeted therapy” trials. As mentioned,
blockade of both HER2 and IGF-IR may have benefit in preclinical systems. It is also highly likely that blockade of IGF-IR and downstream signaling events (MAPK, Akt, etc), could be synergistic. Given the complexity of the cross-talk and feedback between these systems, preclinical studies should also be able to guide us with designing the optimal therapies.
However, it is clear that anti-IGF therapies will soon find their way into clinical trials. Hopefully, the vast experience with preclinical model systems will guide us in the optimal development of these agents.
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