The insulin-like growth factor signaling pathway is important in many human cancers based on data from experimental models as well as epidemiological studies. Important therapies targeted at this pathway have been or are being developed, including monoclonal antibodies to the insulin-like growth factor-I receptor and small molecule inhibitors of the tyrosine kinase function of this receptor. These investigational therapies are now being studied in clinical trials. Emerging data from phase I trials are encouraging regarding the safety of the monoclonal antibodies. In this manuscript, the rationale for targeting the insulin-like growth factor system is reviewed in addition to a summary of the available clinical trial data.
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"Activation of the IGF pathway, by binding of the growth factors IGF-I and IGF-II to the receptors IGF-IR and IR, respectively, triggers complex signaling cascades that regulate cell growth, survival, proliferation, and differentiation in developmental stages . Increased activation of IGF-I system is involved in many pathogenesis of various human cancers including breast, prostate, lung, and colon can- cer . This system is also known to play a crucial role in resistance to cancer therapies by preventing apoptosis, enhancing cell proliferation, and inducing expression of VEGF . "
[Show abstract][Hide abstract]ABSTRACT: Novel concepts and understanding of receptors lead to discoveries and optimization of many small molecules and antibodies as anti-cancerous drugs. Receptor tyrosine kinases (RTKs) are such a promising class of receptors under the investigation in past three decades. RTKs are one of the essential mediators of cell signaling mechanism for various cellular processes. Transformations such as overexpression, dysregulation, or mutations of RTKs may result into malignancy, and thus are an important target for anticancer therapy. Numerous subfamilies of RTKs, such as epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptors, insulin-like growth factor receptor, and hepatocyte growth factor receptor, have been being investigated in recent years as target for anticancer therapy. The present review focuses several small molecules drugs as well as monoclonal antibodies targeting aforesaid subfamilies either approved or under investigation to treat the various cancers.
"Moreover, despite the potential of enhanced therapeutic efficacy immunoliposomal preparations provide over unmodified liposomes the feasibility of personalized targeting approaches. In recent years, the IGF1R has been suggested to be a promising target for different human cancers[12,35]. Accordingly, IGF1R inhibitors were evaluated in preclinical and early clinical trials. However, although antitumoral activity of these agents has been demonstrated for several tumor entities there is a growing body of evidence that receptor blockage alone is not sufficient to induce a potent and sustained effect on tumor growth. "
[Show abstract][Hide abstract]ABSTRACT: Due to the inability of classical chemotherapeutic agents to exclusively target tumor cells, these treatments are associated with severe toxicity profiles. Thus, long-circulating liposomes have been developed in the past to enhance accumulation in tumor tissue by passive targeting. Accordingly, commercially available liposomal formulations of sterically stabilized liposomal doxorubicin (Caelyx®, Doxil®, Lipodox®) are associated with improved off-target profiles. However, these preparations are still not capable to selectively bind to target cells. Thus, in an attempt to further optimize existing treatment schemes immunoliposomes have been established to enable active targeting of tumor tissues. Recently, we have provided evidence for therapeutic efficacy of anti-IGF1R-targeted, surface modified doxorubicin loaded liposomes. Our approach involved a technique, which allows specific post-modifications of the liposomal surface by primed antibody-anchor conjugates thereby facilitating personalized approaches of commercially available liposomal drugs. In the current study, post-modification of sterically stabilized liposomal Dox was thoroughly investigated including the influence of different modification techniques (PIT, SPIT, SPIT60), lipid composition (SPC/Chol, HSPC/Chol), and buffers (HBS, SH). As earlier in vivo experiments did not take into account the presence of non-integrated ab-anchor conjugates this was included in the present study. Our experiments provide evidence that post-modification of commercially available liposomal preparations for active targeting is possible. Moreover, lyophilisation represents an applicable method to obtain a storable precursor of surface modifying antibody-anchor conjugates. Thus, these findings open up new approaches in patient individualized targeting of chemotherapeutic therapies.
"Binding of an IGF to its receptor induces autophosphorylation of the receptor, stimulation of intrinsic tyrosine kinase activity, and phosphorylation of cellular substrates including insulin receptor substrate 1 (IRS-1), leading to gene activation and ultimately to proliferation or differentiation of cells . Two distinct signal transduction pathways for IGF-IR with major roles in transmitting the cellular effects of IGFs have been identified: the Ras/Raf/MAPK and the PI3K/Akt pathways [155, 162]. PI3K, which is also a Ras mediator, phosphorylates the D3 position of phosphatidylinositol on PI4P and PI(4,5)P 2 to produce PI(3,4)P 2 and PI(3,4,5)P 3 . "