IGF-1R INHIBITION AND CANCER TREATMENT

by Selleckchem | Aug 05 2012

SIGNALING IN CANCER:
In humans a gene IGF-I encodes a protein known as insulin like growth factor 1 or abbreviated as IGF-1, this is also known as sulfation factor or Somatomedin. The name related to insulin is due to the structural similarities with insulin. This protein is responsible for the activation of a signaling pathway downstream to it and this is done by triggering IGF receptor known as IGF-1 receptor which is a transmembrane receptor. This receptor plays important roles in aging and insulin signaling but many reports are also there which have proven the connection of IGF1-R with many cancers for example prostate cancer, lung cancer and breast cancer as well. This receptor also provides resistance against chemotherapy and radiotherapy, hence showing anti-apoptotic characteristics. To this statement one example is of breast cancer where EGFR inhibitors such as Erlotinib are used for the EGFR signaling pathway checking but here IGF1-R produces resistance against Erlotinib by the formation of a heterodimer which tends the EGFR pathway continue regardless the presence of inhibitor. The link between EGFR and IGF-R is also noted in the breast cancer where angiogenesis resulted in the tumor invasion or metastasis. So, inhibition to IGF1-R is a way to abrogate many signaling pathways leading to malignancies.
There are many reports about patients suffering from metastatic and primary prostate cancers where an over expression of IGF1-R was noted, for this an effective way to treat cancer is the use of IGF1-R inhibitors. As the signaling pathway of IGF1-R is required for the survival and growth of prostate cancerous cells upon high levels of androgen, the implication of IGF1-R specific inhibitor may be an effective therapy against progression of prostate cancer. In models of mammary tumors of canine animals also have shown the role of IGF and IGFR which ensures the use of IGF1-R inhibitor.

IGF1-R INHIBITORS:
Many of the IGFR inhibitors are available commercially for using in laboratory and research purposes. There are good numbers of IGF1-R agonists and IGF1-R antagonists are routinely used such as LL-37 [1] in research laboratories to demonstrate the role of IGF1-R signaling pathway in many other important cellular pathways and many other molecules playing their role in tumor formations. These IGF1-R inhibitors are easily available from any of the suppliers and costs are moderate to endorse their use in preclinical and ultimately clinical testing. As discussed above the structural similarity of IGFR and IR that is insulin receptor is high in the TK (tyrosine kinase) region and ATP (andenosine triphosphate) binding sites, hence the design of IGF1-R specific inhibitors is not easy. There are three main types of IGF1-R inhibitors which are frequently used are Pyrrolo-(2,3-d)-pyrimidine derivatives and Tyrphostins. The third type is monocloncal antibodies which have proven to be specific therapeutic molecules checking IGF1-R functions and one example is Figitumumab.

IGF-1R INHIBITORS IN CLINICS:
Figitumumab was developed by Pfizer and it is also called as CP-751871 that is being used for many cancer types such as NSCLC or non-small cell lung cancer [2] and adrenocortical cancer [3]. Likely Figitumumab another antibody molecule acting as IGF1-R inhibitor is R1507 which is undergoing clinical trials phase I where patients with advanced solid tumors are being treated [4]. One of the strong IGF1-R inhibitors is tyrphostin AG538 which acts in a dose dependant manner and stops autophosphorylation of IGF1-R resulting in its signaling blockage [5]. A nanomolar inhibitor of IGF1-R is NVP-AEW541 in enzymatic and cell based assays. The highly anticipated result will be there upon success of preclinical and clinical studies of IGF1-R inhibitors.

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
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.
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.