IGF-1R INHIBITOR IN CANCER TREATMENT

by Selleckchem | Aug 27 2012

SIGNALING CASCADE AND DEVELOPMENT OF CANCER:
Insulin like growth factor 1 is one of the signaling molecules in the human cells abbreviated as IGF-I also known as somatomedin or sulfation factor. As the name indicates, the structure of the protein resembles insulin and is responsible for stimulating a signaling cascade via a transmembrane receptor protein i.e., IGF-1 receptor. This receptor is very important due to its role in the process of insulin signaling and aging. This preceptor has also been connected with different types of cancers e.g., prostate cancer, breast cancer and lung cancer. This receptor has been found to provide resistance to the cells against radiotherapy and chemotherapy and hence shows anti-apoptotic characteristics. One example of such resistance is that of Erlotinib, EGFR inhibitors which is used against breast cancer and inhibits EGFR signaling pathway but IGF1-R in these cells produces resistance against the drug. It has been reported to form heterodimers that tend the EGFR pathway to continue rather than inhibiting it. This relationship between IGF-R and EGFR has been studied in breast cancer and the development of metastasis or tumor invasion by angiogenesis was reported. Therefore, inhibiting IGF1-R can be a way to prevent lots of signaling cascades towards malignancies.
Many reports are there that show the presence of overexpressed IGF-1R especially in case of primary and metastatic type of prostate cancer, therefore IGFR inhibitors are needed to be developed and used in order to get a promising therapy against cancer. Signaling of IGF-1R upon stimulation by high levels of androgens helps cancerous cells in survival and growth; therefore anti-IGF-1R therapy would be quite effective in preventing the progression of cancer. In case of mammary tumors in animal models of canines, IGF and IGF-1R was also seen to play some role hence ensured the anti-IGF-1R therapy.

INHIBITORS OF IGF1-R:
Many different types of IGFR agonists and antagonists are discovered by screening of chemical library commercially available that are used for laboratory or research purpose routinely. LL-37 is one of the examples [1] that are used in laboratories to elaborate the part of IGF-1R plays in cell signaling and its role in different cellular processes and in the development of cancer. These inhibitors can easily be bought from the suppliers of the drug in reasonable prices for use in laboratory for preclinical and clinical trials. As IGF-1R resembles IR i.e., insulin receptors, therefore design of inhibitors specifically against IGF-1R is difficult. Both are tyrosine kinase receptors having ATP binding site and tyrosine kinase region. Three more common types of IGF-1R inhibitors available are Tyrophostins, monoclonal antibodies and Pyrrolo-(2,3-d)-pyrimidine derivatives. Monoclonal antibodies have proved to have quite specific in their action and Figitumumab is an example of it.

CLINICAL TRIALS AND IGF-1R INHIBITORS:
Pfizer is the manufacturing company of Figitumumab that has also commercialized it as CP-751871. This drug is being used against different types of cancers for example adrenocortical cancer [3] and non-small cell lung cancer or NSCLC [2]. Similarly another Figitumumab antibody named R1507 is going through phase I clinical trial in order to use it as an IGF1-R inhibitor in the patients having advanced solid tumors [4]. Tyrphostin AG538 is a strong anti-IGF-1R agent that acts in dose dependent way and as far as mode of action is concerned it stops signaling through IGF-1R by blocking autophosphorylation of the receptor [5]. For cell based and enzymatic assays a nanomolar IGF-1R inhibitor is used i.e., NVP-AEW541. For most anticipated results clinical trials on IGF-1R inhibitor are awaited.

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.