Biological Rationale and Current Clinical Experience With Anti-Insulin-Like Growth Factor 1 Receptor Monoclonal Antibodies in Treating Sarcoma

Abstract

Two decades have elapsed since insulin-like growth factor-1 receptor (IGF-1R) signaling was initially implicated in sarcoma biology to the first clinical experience of IGF-1R blockade in sarcoma. During these 21 years, the IGF pathway and its key mediator IGF-1R have been implicated in the genesis, growth, proliferation, metastasis, and resistance to conventional treatment in several sarcoma subtypes. In addition, IGF-1R has been validated, both in vitro and in vivo, as a target for the treatment of sarcoma. Several radiologic and clinical responses to IGF-1R monoclonal antibodies have been reported in Ewing sarcoma patients enrolled in early clinical studies. Furthermore, these therapies were well tolerated, and thus far severe toxicity has been rare. The early clinical evidence of antitumor activity has supported the initiation of various phase II clinical trials in Ewing and other sarcoma subtypes, the results of which are eagerly awaited, as well as studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies. Despite these encouraging results, not all patients benefit from IGF-1R inhibition and consequently there is an urgent need for the identification of predictive markers of response.

Clinical benefit of early phase clinical trial participation for advanced sarcoma patients

“…Other emerging molecularly targeted drugs have shown promising results in early trials, such as IGF1-R (Insulin-like Growth Factor-1 Receptor) monoclonal antibodies in Ewing's sarcoma [8].…”

Targeting of Insulin-Like Growth Factor Type 1 Receptor in Ewing Sarcoma: Unfulfilled Promise or a Promising Beginning?

“…Expression of IGF ligands and IGF-1R in these tumors has long suggested that the pathway is activated via an autocrine loop. 4,5 Importantly, malignant transformation induced by the pathognomonic ESFT EWS/FL-1 fusion gene (product of t(11;22)) is dependent on IGF-1R. 6 The EWS/FL-1 fusion also promotes IGF-1R activation by repressing the expression of IGFBP-3, a binding protein that negatively regulates IGF-1R signaling by sequestering IGF-1 in the serum.…”

Systematic Therapy for Unresectable or Metastatic Soft-Tissue Sarcomas: Past, Present, and Future

“…Minimal activity (2.4% ORR and 26% SD in 167 patients) was seen in other STS subtypes [111,112]. Several other IGF-1R monoclonal antibodies are currently being tested in sarcoma patients; these efforts were recently reviewed [113].…”