Proteomic analysis of combined IGF1 receptor targeted therapy and chemotherapy identifies signatures associated with survival in breast cancer patients

Abstract

Clinical, epidemiological and experimental data identified the insulin-like growth factor-1 receptor (IGF1R) as a candidate therapeutic target in oncology. While this paradigm is based on well-established biological facts, including the potent antiapoptotic and cell survival capabilities of the receptor, most Phase III clinical trials designed to target the IGF1R led to disappointing results. The present study was aimed at evaluating the hypothesis that combined treatment composed of selective IGF1R inhibitor along with classical chemotherapy might be more effective than individual monotherapies in breast cancer treatment. Analyses included comprehensive measurements of the synergism achieved by various combination regimens using the CompuSyn software. In addition, proteomic analyses were conducted to identify the proteins involved in the synergistic killing effect at a global level. Data presented here demonstrates that co-treatment of IGF1R inhibitor along with chemotherapeutic drugs markedly improves the therapeutic efficiency in breast cancer cells. Of clinical relevance, our analyses indicate that high IGF1R baseline expression may serve as a predictive biomarker for IGF1R targeted therapy. In addition, we identified a tengenes signature with potential predictive value. In conclusion, the use of a series of bioinformatics tools shed light on some of the biological pathways that might be responsible for synergysm in cancer therapy.

The Olfactory Receptor Gene Product, OR5H2, Modulates Endometrial Cancer Cells Proliferation via Interaction with the IGF1 Signaling Pathway

“…Combined, the above findings provide a foundation to the postulate that the IGF1R represents a candidate therapeutic target in oncology [7]. The identification of biomarkers that may help in selecting patients and monitoring response to IGF1R-directed therapy is of cardinal importance in gynecologic oncology [44].…”

“…As alluded to above, the identification of biomarkers that can contribute to the successful delivery of IGF1R-directed therapies is of major importance in clinical oncology [47][48][49]. The identification of OR5H2 as an IGF1-dependent, mitogenic factor in endometrial cancer might help in these efforts [44]. The fact that OR5H2 is under-represented in LS, a genetic condition associated with cancer protection, provides further support to the concept that OR5H2 has an important role in the biology of cancer.…”

Hallmarks of cancer: The insulin-like growth factors perspective

“…Unfortunately, most clinical trials led to disappointing results and it is nowadays clear that a combined approach aimed against the IGF axis along with additional pathway/s should lead to a better outcome ( 181 ). A recent pre-clinical study provided evidence that co-treatment of breast cancer cells with AEW541 (a selective IGF1R inhibitor) along with gemcitabine (a chemotherapeutic drug) improved the treatment efficiency ( 31 ). The degree of synergy achieved, as expressed in combination index values, was very strong.…”

“…The unprecedented gain-of-knowledge generated by post-genomic technologies is allowing us to analyze physiological and pathological processes at a level of integration that was, until recently, unthinkable ( 23 , 24 ). Given that the IGF axis and, particularly, the IGF1R emerged in recent years as promising therapeutic targets in oncology, the identification of signaling networks linked to IGF1 action (‘ IGF1 signatures ’) is expected to be of major importance on our ability to optimize interventional tools for the manipulation of this endocrine system ( 25 – 31 ). Furthermore, combined omics analyses will most certainly impinge on our capacity to predict responsiveness to selective IGF1R-directed drugs ( 32 , 33 ).…”

The IGF1 Signaling Pathway: From Basic Concepts to Therapeutic Opportunities

“…The IGF network is recognized as a potential molecular target in cancer therapy and attempts are being made to translate preclinical results into medical protocols [23][24][25][26][27]. The aim of the present review article is to provide an updated overview of the IGF network, with a special emphasis on intracellular signaling events.…”