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The importance of the IGF-signaling receptors, IGF1R and IR, in cancers and the possible ways to interrupt the pathways

Boiten, T.A.J. (2009) The importance of the IGF-signaling receptors, IGF1R and IR, in cancers and the possible ways to interrupt the pathways. Bachelor's Thesis, Biology.

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Insulin-like growth factors (IGFs) and insulin are main regulators of cell growth in human and in animals. IGFs can bind to the IGF-receptors (IGF1R and IGF2R) or to the insulin receptor (IR). Insulin can only bind to the IR. Whereas there is only one type of IGF1R and IGF2R, two isoforms of IR exists, IR-A and IR-B. The IGFs- and Insulin receptors contains both two dimers with an extracellular alfa- and two intracellular beta domains. The IGF1R and IR can also form heterodimers with each other, the so called hybrids. IGFs and their signal transducing receptors are thought to have an important role in carcinogenesis and in the resistance of cancers against chemotherapy. There is evidence that cancers up-regulate the expression of IGF-I and II. Additional data show that cells survive and escape from chemotherapy when IGF-I is added. Mainly, the IR-A plays a keyrole in IGF signaling. IR-A and also the hybrid form with IGF1R (HR-A) are over-expressed in neoplastic tissue. This last form especially has to be blocked because it facilitates more binding sites for IGFs, by binding IGF-I and II and insulin all with high affinity. Discussed in this paper are the ways to block IR-A and HR-A, by making a comparison to the methods used by blocking the IGF1R. The major inhibitors that are hopeful in IR-A and HR-A blocking are the tyrosine kinase inhibitors, antibodies or IGF binding proteins (IGFBPs). There are no equal recommendations for the blockade of the IR-A/HR-A in all cancers as a result of different characteristics of every cancer. Promising IR-blocking ways for two of the most occurring cancers, breast and lung cancer, are elucidated. The use of a specific small molecule inhibitor INSM18, might have beneficial effects in the treatment of breast cancer, because this tyrosine inhibitor has also activity against the human epidermal growth factor receptor (HER2). Known is that HER2 often is up-regulated in breast cancer. For lung cancer there is evidence that a specific antibody (mAb) CP751,871 (against IGF1R) in combination with chemotherapy causes higher response rates. It might be important that also the IR-A and HR-A are targeted. This could be done by addition of small molecule inhibitors in low concentrations and antibodies. Nowadays, mAbs against IGF1R are used, but also mAbs against IR-A must be developed. Low concentrations of tyrosine kinase inhibitors must be used so IR-B is not blocked totally (because all receptors IGF1R, IR-A, IR-B, HR-A, HR-B are then blocked) but the levels are high enough to make the blocking of IR-A, IGF1R and HRA more sensitive.

Item Type: Thesis (Bachelor's Thesis)
Degree programme: Biology
Thesis type: Bachelor's Thesis
Language: English
Date Deposited: 15 Feb 2018 07:30
Last Modified: 15 Feb 2018 07:30

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