Targeting insulin-like growth factor-1 receptor in cancer

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Oncology-Pathology

Sammanfattning: Cancer is a multi-step process where the accumulation of several genetic and epigenetic alterations drives the transformation of a normal cell to a malignant cell, skipping the normal control of defense, repair and apoptosis. During the selection process towards a malignant phenotype, the transforming cells make use of normal (physiological) extracellular signaling pathways to create growth advantage over normal cells. In this context, insulin-like growth factor 1 receptor (IGF-1R) emerges as an important factor responsible for the transformation and proliferation of malignant cells. IGF-1R confers protection against apoptosis, maintains the malignant phenotype, and defends against antitumor therapy. In contrast, the IGF-1R is not an absolute requirement for normal cell growth. The multiple functions of IGF-1R in cancer development coupled with its redundancy in maintaining cell growth make this receptor an attractive target for cancer treatment. Until recently there were multiple strategies to block the IGF-1R pathway in order to prevent growth and to increase apoptosis of malignant cells. However, none of them has so far presented the necessary requirements for clinical use. In this context, co-inhibition of the highly homologous insulin receptor cannot be accepted for a pharmaceutical agent. This study presents two different principles to specifically target the IGF-1R One is to modulate physiological mechanisms to degrade and therewith inactivate the receptor. This approach is still at a basic research level. The other principle is a small molecule strategy to reduce the catalytic activity of IGF-1R. Relating to the first principle, we recently showed that the oncoprotein MDM2 serves as a ligase (E3) in ubiquitination of IGF-1R. We demonstrated a physical association of IGF-1R to MDM2 and that a mixture of MDM2 and IGF-1R in an in vitro assay resulted in ubiquitination of IGF-1R. IGF-1R. In cultured cells, an increase in MDM2-mediated IGF-1R ubiquitination caused degradation of the receptor and induced cell death. The IGF-1R ubiquitination may be involved in receptor function and open the possibility of modulating this processing to block the receptor activity and therewith cause tumor regression. Relating to the second principle, we identified a small molecule (PPP) that specifically inhibited tyrosine phosphorylation of IGF-1R and induced apoptotic cell death in a selective manner. PPP interfered with the activation loop of the receptor kinase and did not affect the ATP binding. It decreases the activities of the two major signaling pathways (P13K and MAPK pathway) in an IGF-1R I specific manner and provoked a strong G2 arrest in vitro systems. It had a remarkably inhibitory effect in tumor growth in vivo and decreased the metastasis potential both in vivo and in vitro in IGF-1R 1 positive tumor cells. The obtained results of this thesis highlight the possibility to target the IGF-1R as a therapeutic option for cancer.

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