Igf News.
IGF Receptor-1 Kinase Inhibitors.
The insulin and the IGF-1 pathway are closely intertwined. Both can bind the insulin receptor or the IGF receptor 1 (IGFR-1). IGF-2, on the other hand, can bind either IGFR-1 or the high-affinity IGFR-2, which, however, does not mediate intracellular signals and is thus considered a "sink" for IGF-2.
Signaling through IGFR-1 in normal cells leads to the activation of multiple intracellular pathways, mediated by the receptor-associated tyrosine kinase domain, by PI-3 kinase, and by serine/threonine kinase (Akt), yielding growth and enhanced survival. In cancer cells, IGFR-1 plays an even more critical role because it contributes to the promotion of tumor growth by inhibition of the apoptosis, transformation, metastasis, and induction of angiogenesis through the vascular endothelial growth factor (VEGF).[1-3]
As illustrated by Francesco Hofmann, PhD,[4] of Novartis Pharma (Basel, Switzerland), increased levels of circulating IGF-1 have been detected in patients with breast and prostate cancers, secondary to an increased expression in the tumor tissues. Elevated levels of IGF-2 and IGFR-1 have been linked to tissue invasion and the establishment of metastasis. In vitro, overexpression of IGFR-1 is sufficient to transform NIH-3T3 fibroblasts, and it is critically involved in the transformation process mediated by oncogenes.[4,5]
A number of strategies have been used to assess the functional relevance of the IGF system in cancer and to provide proof of principle that inhibition of these pathways may have beneficial antitumor effects. Dominant negative mutants, kinase domain mutants, antisense oligonucleotides, and particularly antagonistic antibodies (19D12, h7C10, and BsAb) and small-molecule tyrosine kinase inhibitors are being evaluated for their ability to block signaling and, hence, the survival and growth of cancer cells. For most, activity was shown by the ability of these agents to reverse transformation in tumor cell lines in vitro and to increase sensitivity to chemotherapy and irradiation. Similar inhibitory effects on tumor cell growth and metastasis were seen in vivo, in experimental animal models.[4]
As noted by Dr. Hofmann, the high homology existing between the insulin receptor and the IGFR-1 kinase domains makes the design of IGFR-1 specific inhibitors (to avoid impairment of the insulin receptor pathway) a substantial challenge. The fact, however, that staurosporine can discriminate between these 2 receptors indicates that selectivity can be reached, to some extent. Further studies have shown that some tyrphostins have a moderate degree of selectivity for IGFR-1 and that cyclolignans show single-agent activity in animal tumor models.
Screening of a large library of compounds by high throughput screening led to the identification of pyrrolo[2,3-d]-pyrimidine as a cellular inhibitor of the IGFR-1 tyrosine kinase. In vitro kinase assays of the related compound NVP-AEW541 showed that it inhibited both the recombinant IGFR-1 kinase domain and the homologous domain in the insulin receptor. The IC50 for IGFR-1 in this assay was approximately 150 mM and about 2-3-fold higher for the kinase domain of Flt-1, 2, and 3.[4]
A preferential inhibition of the IGFR-1 kinase vs the insulin receptor kinase domain (27-fold higher for IGFR-1) was, however, seen when NVP-AEW541 was tested in a cellular system. The reason for this different selectivity profile is at the moment unclear, but Dr. Hoffman hypothesized the existence of differences in the 3-dimensional structures of the 2 kinase domains in vivo and in vitro, which would lead to the different selectivity profile seen in cells vs the isolated kinase assays. The IC50 of NVP-AEW541 in cells was .086 mcM for IGFR-1 vs 2.3 mcM for the insulin receptor and > 10 mcM for HER-2/neu.[4]
Functional testing of NVP-AEW541 showed that it inhibited IGF-1-mediated survival and anchorage-independent growth in the breast carcinoma cell line MCF-7. A block of IGF-related kinase activity also was observed in vivo in mice carrying subcutaneous tumor xenografts. Inhibition of the IGFR-1-driven growth of fibrosarcoma cells occurred in a dose-dependent fashion in the presence of NVP-AEW541. Residual tumor growth was, however, present in treated animals.
Selectivity in receptor kinase targeting was further confirmed by clinical chemistry measurements. No changes were observed in plasma glucose and insulin levels. Histopathology exams did not reveal any abnormality in the liver, kidneys, pancreas, brain, major lymph nodes, heart, and skeletal muscle.[4]
Further development of NVP-AEW541 is now in progress, as noted by Dr. Hoffman, in collaboration with oncologists at the Dana Farber Institute (Boston, Massachusetts), with the aim of treating multiple myeloma (MM) patients. In vitro studies, in fact, have shown that IGF-1 can induce the proliferation of MM cells, and cancer cells from MM patients express IGFR-1.
Partial inhibition of proliferation (30% to 60%) and reduced in vitro survival has been achieved by targeting MM cells in vitro with NVP-AEW541, suggesting a potential benefit in vivo for patients with MM. When the inhibitor was tested in a mixed culture of CD138+ MM and bone marrow-derived stromal cells, only the CD138+ cells were killed by the inhibitor, and no effect was seen on the stromal cells.[4] Further evaluation of other bone marrow- and tissue-derived normal cells will give a more complete profile of its tolerability and safety.
In vivo studies with a bioluminescent detection system in mice showed that a combination with dexamethasone, doxorubicin, or melphalan delayed and/or decreased the progression of tumor growth in treated animals. With the combination of melphalan and NVP-AEW541, about 50% of animals were still alive after 40 days vs none of the control group. Longer-term studies will clarify to which extent treatment with NVP-AEW541 simply delays or indeed substantially decreases tumor growth.[4]
Of note, subsets of small-cell lung cancer that are usually quite resistant to a number of antitumor agents express a SCF/c-Kit-mediated autocrine loop. IGF-1 as well as SCF are known to be strong stimulators of PI-3 kinase and Akt kinase in small-cell lung cancer. Thus, in the hypothesis proposed by Dr. Hoffman, a combination targeting these 2 growth pathways may achieve a synergistic effect through inhibition of growth and induction of apoptosis in those cell subsets that express functional IGFR-1 and c-Kit.
Further clinical testing will be performed with tumors of the pancreas, colon, breast, and prostate, among others, to evaluate whether NVP-AEW541 as a single agent or in combinations represents a good addition for the targeted inhibition of cancer cell growth and survival.
6-4-2004.
JUST FOR EDUCATIONAL PURPOSE .
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Originally Posted by oswaldosalcedo
