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IGFR
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IGFR(8)

The tetrameric transmembrane RTK IGF1R was identified in 1986.(1) This pathway leads to the activation of PI3K to promote cell growth, proliferation, differentiation, survival and migration.(2-4) IGFs and their receptors comprise a signalling system required for G1/S phase cell-cycle progression and cell division. The IGF system includes three ligands - IGF1, IGF2 and insulin - that interact with IGF1R, IGFR2, and IR.(1, 5) The binding of IGF1, IGF2, or insulin to IGF1R leads to the autophosphorylation of tyrosines in the kinase domain on the intracellular portion of the b-subunits, inducing the phosphorylation of juxtamembrane tyrosines and carboxyl-terminal serines. These substrates initiate the PI3K/Akt and RAS/RAF/MEK/ERK signalling pathways, transmitting the IGF1R signal.(1) Phosphorylated IRS1 recruits the regulatory and catalytic subunits of PI3K, ultimately resulting in the downstream phosphorylation of Akt.(6) It is well known that Akt plays a critical role in controlling survival and apoptosis. Akt phosphorylation enhances the protein synthesis required for cell proliferation via the mammalian target of rapamycin complex, triggers the anti-apoptotic effects of IGF1R through the phosphorylation and inactivation of Bcl-xL/Bcl-2 associated death promoter and the inactivation of caspase 9, and also stimulates cell growth through the inhibitory phosphorylation of growth factors (including forkhead box proteins, p21, p27, Chk1, and glycogen synthase kinase 3 (GSK3)).(1) In parallel to PI3K-driven signalling, the recruitment of growth factor receptor bound protein 2 (Grb2)/SOS by either phosphorylated IRS1 or SHC leads to IGF1R signal transmission via the RAS/RAF/MEK/ERK pathway.(7) The Grb2/ SOS complex activates the signalling pathway, resulting in the downstream phosphorylation and activation of MKK and ERK. Activated ERK induces cell proliferation by the phosphorylation of nuclear transcription factors such as Ets-like transcription factor-1 (Elk-1) and c-Fos. Activated MKK phosphorylates p38, and is responsible for inducing cell proliferation via the activation of c-Myc, JNK, and subsequently c-Jun.(1)
IGF1R is an attractive target for cancer therapy as its abnormal expression is associated with the formation of tumors, metastasis, and treatment resistance.(1, 5) The three main approaches are receptor blockade with mAbs, TYK inhibition, and ligand neutralization via mAbs targeted to ligand or recombinant IGF binding proteins.(5) MAbs directed against IGF1R cannot block the binding of both IGF1 and IGF2, nor can they down-regulate both IGF1R homo-receptor and hybrid receptor pairs. TKIs indiscriminately inhibit the kinase domains of all IGF system receptors.(1)


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References

1. Haisa M. The type 1 insulin-like growth factor receptor signalling system and targeted tyrosine kinase inhibition in cancer. Journal of International Medical Research. 2013:0300060513476585.

2. Grimberg A. Mechanisms by which IGF-I may promote cancer. Cancer Biology and Therapy. 2003;2(6):630-5.

3. Cohen DH, LeRoith D. Obesity, type 2 diabetes, and cancer: the insulin and IGF connection. Endocrine-related cancer. 2012;19(5):F27-F45.

4. Panda AC, Grammatikakis I, Yoon J-H, Abdelmohsen K. Posttranscriptional Regulation of Insulin Family Ligands and Receptors. International journal of molecular sciences. 2013;14(9):19202-29.

5. Arnaldez FI, Helman LJ. Targeting the insulin growth factor receptor 1. Hematology/oncology clinics of North America. 2012;26(3):527-42.

6. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098-101.

7. Perrini S, Laviola L, Carreira MC, Cignarelli A, Natalicchio A, Giorgino F. The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis. Journal of Endocrinology. 2010;205(3):201-10.

8. Yi J-S, Park JS, Ham Y-M, Nguyen N, Lee N-R, Hong J, et al. MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling. Nature communications. 2013;4.

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Thursday, September 15, 2016 6:45 AM|Xiao, Q., Zhou, D., Rucki, A. A., Williams, J., Zhou, J., Mo, G., Murphy, A., Fujiwara, K., Kleponis, J., Salman, B., Wolfgang, C. L., Anders, R. A., Zheng, S., Jaffee, E. M., Zheng, L.|Cancer Research recent issues|Labels: IGFR, STAT, pancreatic cancer
Stromal fibrosis is a prominent histologic characteristic of pancreatic ductal adenocarcinoma (PDAC), but how stromal fibroblasts are regulated in the tumor microenvironment (TME) to support tumor growth is largely unknown. Here we show that PDAC cells can induce DNA methylation in cancer-associated fibroblasts (CAF). Upon direct contact with PDAC cells, DNA methylation of SOCS1 and other genes is induced in mesenchymal stem cells or in CAF that lack SOCS1 methylation at baseline. Silencing or decitabine treatment to block the DNA methylation enzyme DNMT1 inhibited methylation of SOCS1. In contrast, SOCS1 gene methylation and downregulation in CAF activated STAT3 and induced insulin-like growth factor-1 expression to support PDAC cell growth. Moreover, CAF facilitated methylation-dependent growth of PDAC tumor xenografts in mice. The ability of patient-derived CAF with SOCS1 methylation to promote PDAC growth was more robust than CAF without SOCS1 methylation. Overall, our results reveal how PDAC cells can reprogram CAF to modify tumor–stromal interactions in the TME, which promote malignant growth and progression. Cancer Res; 76(18); 5395–404. ©2016 AACR.
Wednesday, September 14, 2016 5:17 PM|Andreas Hilgeroth|RSC - Med. Chem. Commun. latest articles|Labels: EGFR, IGFR

Med. Chem. Commun., 2016, Advance Article
DOI: 10.1039/C6MD00329J, Research Article
Cornelius Hempel, Abdulkarim Najjar, Frank Totzke, Christoph Schachtele, Wolfgang Sippl, Christoph Ritter, Andreas Hilgeroth
Small-molecule inhibitors of cancer-relevant receptor tyrosine kinases EGFR and IGF-1R have been discovered.
To cite this article before page numbers are assigned, use the DOI form of citation above.
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Wednesday, August 31, 2016 10:05 PM|Beauvais, D. M., Jung, O., Yang, Y., Sanderson, R. D., Rapraeger, A. C.|Cancer Research recent issues|Labels: IGFR, MM
Syndecan-1 (Sdc1/CD138) expression is linked to disease severity in multiple myeloma, although the causal basis for this link remains unclear. Here we report that capture of the IGF1 receptor (IGF1R) by Sdc1 suppresses ASK1-dependent apoptosis in multiple myeloma cells. Sdc1 binds two different fractions of IGF1R, one that is constitutively active and a second that is activated by IGF1 ligand. Notably, IGF1R kinase activity in both fractions is blocked by synstatinIGF1R (SSTNIGF1R), a peptide that inhibits IGF1R capture by Sdc1, as well as by a truncated peptide (SSTNIGF1R-T) that appears to be specific for multiple myeloma cells. Mechanistically, we show that ASK1 is bound to active IGF1R and inhibited by Tyr and Ser83/Ser966 phosphorylation. When IGF1R engagement with Sdc1 is blocked by SSTNIGF1R, ASK1 becomes activated, and initiates JNK- and caspase-3–mediated apoptosis. In pharmacologic tests, we find SSTNIGF1R is highly stable in human plasma and displays a half-life of 27 hours in mice, wherein it significantly reduces both the size and neovascularization of CAG myeloma tumor xenografts. Taken together, our results offer a preclinical proof of concept and mechanistic rationale for the exploration of SSTNIGF1R as an experimental therapeutic to dually attack multiple myeloma tumor cell survival and tumor angiogenesis. Cancer Res; 76(17); 4981–93. ©2016 AACR.
Thursday, July 28, 2016 7:56 AM|Lee, J.-S., Lee, H.-Y.|Cancer Research recent issues|Labels: IGFR
Drug resistance is a major impediment in medical oncology. Recent studies have emphasized the importance of the tumor microenvironment (TME) to innate resistance to molecularly targeted therapies. In this study, we investigate the role of TME in resistance to cixutumumab, an anti-IGF-1R mAb that has shown limited clinical efficacy. We show that treatment with cixutumumab accelerates tumor infiltration of stromal cells and metastatic tumor growth and, ultimately, decreases overall survival of mice. Cixutumumab treatment stimulates recruitment of macrophages and fibroblasts via STAT3-dependent transcriptional up-regulation of IGF2 in cancer cells and paracrine IGF2/IGF-2R activation, resulting in the stroma-derived CXCL8 production and thus angiogenic and metastatic environment. Silencing IGF2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibits the cancer-stroma communication and angiogenic activities of vascular endothelial cells. These findings suggest that blocking the STAT3/IGF-2/IGF-2R intercellular signaling network may overcome the adverse consequences of anti-IGF-1R mAb-based therapies.Citation Format: Ji-Sun Lee, Ho-Young Lee. Resistance to IGF-1R targeted therapy by insulin-like growth factor 2-mediated tumor microenvironment network. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A36.
Wednesday, July 27, 2016 11:11 AM|KARLIKOVA, M., TOPOLCAN, O., NARSANSKA, A., KUCERA, R., TRESKOVA, I., TRESKA, V.|Anticancer Research recent issues|Labels: IGFR, VEGF, breast cancer

Aim: To evaluate the possibility of selected biomarkers for breast cancer diagnostics and/or treatment monitoring, lymph node (LN) status determination and clinical decision regarding axillary node dissection. Patients and Methods: Two hundred and eleven patients with malignant breast cancer and 42 age-matched healthy controls were enrolled. Serum insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and plasma epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), osteoprotegerin (OPG) and osteopontin (OPN) were measured. We compared patients versus controls, patients with negative versus positive lymph node and patients with and without axillary lymph node dissection (ALND). Results: We found elevated IGF1 and VEGF levels in patients with lymph node metastases compared to controls (p=0.0179 and p=0.0091, respectively) and in patients with ALND (p=0.0337 and p=0.0438, respectively). Conclusion: Circulating IGF1 and VEGF levels may predict the presence of lymph node metastases and help in the decision to avoid ALND in patients with early-stage breast cancer.

Thursday, July 14, 2016 10:05 PM|Vo, K. T., Edwards, J. V., Epling, C. L., Sinclair, E., Hawkins, D. S., Grier, H. E., Janeway, K. A., Barnette, P., McIlvaine, E., Krailo, M. D., Barkauskas, D. A., Matthay, K. K., Womer, R. B., Gorlick, R. G., Lessnick, S. L., Mackall, C. L., DuBois, S. G.|Clinical Cancer Research recent issues|Labels: IGFR, childhood cancer, sarcoma

Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma cells in the blood and bone marrow. These techniques were used to evaluate the prognostic significance of micrometastatic disease in Ewing sarcoma.

Experimental Design: Newly diagnosed patients with Ewing sarcoma were enrolled on two prospective multicenter studies. In the flow cytometry cohort, patients were defined as "positive" for bone marrow micrometastatic disease if their CD99+/CD45 values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or bone marrow samples classified the patients as "positive" or "negative" for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Coexpression of insulin-like growth factor-1 receptor (IGF-1R) on detected tumor cells was performed in a subset of flow cytometry samples.

Results: The median total bone marrow CD99+CD45 percent was 0.0012% (range 0%–1.10%) in the flow cytometry cohort, with 14 of 109 (12.8%) of Ewing sarcoma patients defined as "positive." In the PCR cohort, 19.6% (44/225) patients were "positive" for any EWSR1/FLI1 translocation in blood or bone marrow. There were no differences in baseline clinical features or event-free or overall survival between patients classified as "positive" versus "negative" by either method. CD99+CD45 cells had significantly higher IGF-1R expression compared with CD45+ hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; P < 0.001).

Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with Ewing sarcoma. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest. Clin Cancer Res; 22(14); 3643–50. ©2016 AACR.

CONCLUSIONSThere was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC‐ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371–2378. © 2016 American Cancer Society. (Source: Cancer)
Saturday, March 19, 2016 10:51 AM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: IGFR, CRC
Authors: Dowling CM, Phelan J, Callender JA, Cathcart MC, Mehigan B, McCormick P, Dalton T, Coffey JC, Newton AC, O'Sullivan J, Kiely PA Abstract Despite extensive efforts, cancer therapies directed at the Protein Kinase C (PKC) family of serine/threonine kinases have failed in clinical trials. These therapies have been directed at inhibiting PKC and have, in some cases, worsened disease outcome. Here we examine colon cancer patients and show not only that PKC Beta II is a tumour suppressor, but patients with low levels of this isozyme have significantly decreased disease free survival. Specifically, analysis of gene expression levels of all PKC genes in matched normal and cancer tissue samples from colon cancer patients revealed a striking down-regulation of the gene coding PKC Be...
Monday, February 29, 2016 4:00 PM|BMC Research Notes|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: IGFR, lung cancer
Despite advances in targeted therapy for lung cancer, survival for patients remains poor and lung cancer remains the leading cause of cancer-related deaths worldwide. The type I insulin-like growth factor rece... (Source: BMC Research Notes)