Article

The emerging role of the insulin-like growth factor pathway as a therapeutic target in cancer

Massachusetts General Hospital, LRH 308, 55 Fruit Street, Boston, Massachusetts 02114, USA.
The Oncologist (Impact Factor: 4.87). 02/2008; 13(1):16-24. DOI: 10.1634/theoncologist.2007-0199
Source: PubMed

ABSTRACT

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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    • "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. "
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    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.
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    • "We hypothesized that patients with NAFLD-related HCC have alterations in the IGF pathway that are distinct from those in patients with HCC from other causes, such as viral and alcoholic hepatitis. Identification of upregulated components of the IGF pathway may have potential therapeutic implications for patients who may benefit from treatment with IGF-1R inhibitors, which have shown promising anticancer activity in clinical trials [11]. "
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    ABSTRACT: Background The insulin-like growth factor (IGF) pathway is implicated in the pathogenesis of hepatocellular carcinoma (HCC) and may be important in nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine expression levels of IGFs and receptors in NAFLD-associated HCC. Methods Tissue microarrays were constructed from patients who underwent hepatectomy for HCC. Immunohistochemistry was performed using antibodies for IGF ligands and receptors. Immunostain results were scored by a pathologist blinded to clinical data. Results Among 27 patients with HCC, the most common underlying liver diseases included NAFLD, hepatitis C, and alcoholic hepatitis. Expression levels of IGFs and receptors were not associated with patients’ underlying liver disease. In all patients, IGF-2 expression was upregulated in tumor and adjacent non-neoplastic liver. Expression of IGF-1 was low in adjacent liver in 6 of 10 patients with cirrhosis, compared with 2 of 17 patients without cirrhosis (P = 0.025). Higher IGF-1 expression in liver adjacent to tumor was associated with poorer median survival of 22 months, compared with 72 months with equal or lower IGF-1 expression in adjacent liver relative to tumor (P = 0.006). Conclusions Our preliminary results demonstrate significant associations between IGF-1 expression and liver cirrhosis and survival after resection in patients with HCC, independent of their underlying liver disease.
    Full-text · Article · Jul 2014 · World Journal of Surgical Oncology
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    • "It has been found that IGF1R plays a role in the establishment and maintenance of cellular transformation, itself or its ligands *Address correspondence to this author at the WKL125 442, Novartis, CH- 4002 Basel, Switzerland; Tel: +41616962050; Fax: +41616963835; E-mail: patrick_chene@yahoo.com are often overexpressed in human tumors, its activation protects against apoptosis, favors invasion and metastasis [4] [5]. This makes IGF1R an attractive drug target for anticancer therapy [6] [7], and many drug discovery efforts are ongoing to identify agents that selectively block the IGF1R pathway in tumor cells [4] [5] [6] [7] [8] [9] [10]. The identification of low molecular weight molecules that, upon binding to the kinase domain of IGF1R, inhibit its catalytic activity is one approach under investigation. "
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    ABSTRACT: The insulin-like growth factor-1 receptor (IGF1R) is a drug target for oncology, and many studies are ongoing to identify compounds that inhibit its tyrosine kinase activity. IGF1R is highly homologous to the insulin receptor (IR) and IGF1R inhibition might be beneficial for patients, while IR inhibition may lead to limiting toxicity. Therefore selectivity for IGF1R over IR is the aim for drug design in this context. A few compounds that selectively inhibit IGF1R over IR in cells have been identified, but none of them show the same levels of selectivity in enzymatic assays. To deter-mine whether this discrepancy is linked to the conditions used in the enzymatic assays, we have studied the interaction be-tween known IGF1R inhibitors (NVP-AEW541, OSI906, AG538, NVP-TAE226) and phosphorylated/unphosphorylated IGF1R/IR proteins with both biophysical (isothermal calorimetry and surface plasmon resonance) and enzymatic methods. In this report, we describe the results of this study and comment on the different degrees of selectivity IGF1R versus IR measured in biochemical and cellular assays. Finally, our study provides new information on the biochemical and mechanism of action of these small molecular weight IGF1R inhibitors.
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