IGF-1R INHIBITOR IN CANCER TREATMENT

by Selleckchem | Aug 12 2012

SIGNALING PATHWAY AND CANCER:
One of the important signaling molecules in body of human cells is the Insulin like growth factor 1 and abbreviated as IGF-I and also known as sulfation factor or somatomedin. Structure of this protein, as indicated by the name, resembles insulin and responsible of stimulating a signaling pathway through transmembrane receptor protein i.e., receptor IGF-1. The receptor is very much important for its role in process of aging and signaling of insulin. IGF-1 receptor is also connected to different types of tumors like breast cancer, lung cancer and prostate cancer. It was observed that this receptor offers resistance against chemotherapy and radiotherapy in the cells hence showing the anti-apoptotic activity. An important example of such resistance is Erlotinib, HER-1 inhibitors that is used against breast cancer and causes inhibition of EGFR signaling pathway but IGF1 receptor in cells generates resistance against this drug. The formation of hetrodimers has been reported that stimulate the EGFR cascade to further continue rather than its inhibition. In breast cancer cells, the relation between EGFR pathways and IGF-R was studied and the tumor invasion or metastasis by the angiogenesis was reported. Hence, a bundle of signaling pathways leading towards malignancies can be inhibited by inhibiting the IGF-R.
A lot of reports showed the over expression of IGF-1R, especially in metastatic and primary type of prostate cancer, so IGF1R and IR inhibitors are in need to designed and used against cancers as a good therapeutic tool. IGF-1R signaling stimulated by increased levels of adrogens helps cancer cells in growth and survival. Hence anti-IGF-1R therapy must be a promising and efficient to prevent the progression of cancer. In the animal models of canines, related with mammary tumors, IGF-1R and IGF was also observed to play some important role, therefore ensured anti-IGF-1R therapy.

IGF1-R INHIBITORS:
Different types of agonists and antagonists of IGFR have been discovered by the screening of commercially available chemical compound library used for various research and laboratory purposes in routine. One of the most common example of such chemical agents is LL-37 [1] used in laboratory to reveal part of IGF-1R played in signaling of cell and role in various cellular processes and also in the production of cancer. These drugs can easily be bought from respective suppliers at reasonable prices for the laboratory use in clinical and preclinical trials. IGF-1R has resemblance to IR i.e., insulin receptors therefore it is difficult to design the inhibitors especially against the IGF-1R. These both are the tyrosine kinase receptors exhibiting binding sites and the tyrosine kinase region. Tyrophostins, Pyrrolo-(2,3-d)-pyrimidine derivatives and monoclonal antibodies are the three most common kinds of IGF-1R inhibitors. Figitumumab is an important example of Monoclonal antibodies which have proved themselves very specific in their activity.

IGF-1R INHIBITORS: CLINICAL TRIALS
Figitumumab is the manufacturing company of the drug Pfizer, commercially available as CP-751871 and this drug is now in use against various types of cancer for instance NSCLC or non-small cell lung cancer [2] and adrenocortical cancer [3]. In same way another antibody of Figitumumab named as R1507 is under clinical trials phase I to use this IGF1-R inhibitor for the treatment of advanced solid tumors [4]. Another anti-IGF-1R agent is Tyrphostin AG538 that acts in a dose dependant manner but so far as mode of activity is concerned it inhibits signaling cascade triggered by IGF-1R by blocking the receptor’s autophosphorylation [5]. For the enzymatic and cell based assays nanomolar IGF-1R inhibitor is used that is NVP-AEW541. For the most anticipated results, clinical trials of IGF-1R inhibitor are in process.

REFERENCES:
1. Girnita A, e.a., Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor. Oncogene, 2011.
2. Gualberto A, K.D., Development of the monoclonal antibody figitumumab, targeting the insulin-like growth factor-1 receptor, for the treatment of patients with non-small-cell lung cancer. Clinical Lung Cancer, 2009.
3. Haluska P, e.a., Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer chemotherapy and pharmacology, 2009.
4. Kurzrock R, e.a., A Phase I Study of Weekly R1507, A Human Monoclonal Antibody Insulin-like Growth Factor-I Receptor Antagonist, in Patients with Advanced Solid Tumors. Clin Cancer Res, 2010.
5. Blum G, e.a., Substrate Competitive Inhibitors of IGF-1 Receptor Kinase. Biochemistry, 2000.

Cat.No.	Product Name	Information
S1023	Erlotinib HCl	Erlotinib HCl is an EGFR inhibitor with IC50 of 2 nM in cell-free assays, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.
S1034	NVP-AEW541	NVP-AEW541 is a potent inhibitor of IGF-1R/InsR with IC50 of 150 nM/140 nM in cell-free assays, greater potency and selectivity for IGF-1R in a cell-based assay.