Identification of sensitivity markers for BMS-536924, an inhibitor for insulin-like growth factor-1 receptor

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3506-3506 ◽  
Author(s):  
F. Huang ◽  
W. Hurlburt ◽  
R. Hafezi ◽  
X. Han ◽  
J. Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Protein Profiling ◽  
Egfr Inhibitors ◽  
Synergistic Activity ◽  
Insulin Like Growth Factor ◽  
Molecule Inhibitor ◽  
Key Steps

3506 Background: Insulin-like growth factor-1 receptor (IGF-1R) signaling is an important regulator of mitogenesis, transformation to the oncogenic phenotype and anti-apoptotic effects in malignant cells. Over-expression of IGF-1R, seen in many tumors, may confer a growth advantage or drug resistance. A potent small-molecule inhibitor (BMS-536924) of IGF-1R tyrosine kinase showed anti-tumor activity in sarcoma, prostate, colon and pancreatic tumor models. One of the integral goals in the development of BMS-536924 as a cancer therapeutic is to identify molecular biomarkers predictive of response to the drug that ultimately will aid in selecting the patients who are most likely to benefit. Methods: The sensitivity (IC50) to BMS-536924 was determined for a panel of 29 pediatric sarcoma and neuroblastoma cell lines. Both microarray and LC/MS based protein profiling were utilized to analyze the baseline gene or protein expression level. Drug treatment studies were performed using two rhabdomyosarcoma cell lines, Rh41 (sensitive to BMS-536924) and Rh36 (resistant to the drug) to identify markers that are modulated by BMS-536924. Results: (1). Sixteen out of the 29 cell lines were highly sensitive to BMS-536924; candidate markers that correlated with the sensitivity to BMS-536924 were identified by gene expression and protein profiling. (2). Histological correlation was also discovered, with specific subtypes of sarcoma having a low IC50 to BMS-536924. (3). Pathway analysis noted that some major candidate markers are common key steps in the EGF-R pathway and the IGF1-R pathway. This observation of cross-talk between the two pathways led to the hypothesis of synergy with combined inhibition of both pathways. Combination studies of BMS-536924 and EGFR inhibitors were performed and synergism was observed. (4). Markers modulated by BMS-536924 in a sensitive cell line were identified. Conclusions: This work has identified candidate markers correlating to BMS-536924 sensitivity in vitro. The possible mechanism of synergistic activity of IGF1-R and EGFR inhibitors will be presented. No significant financial relationships to disclose.

scholarly journals P3-016: In vitro activity of picropodophyllin in lung cancer cell lines and association to the insulin-like Growth Factor-1 receptor

2007 ◽  
Vol 2 (8) ◽  
pp. S613-S614
Author(s):  
Joachim Gullbo ◽  
Michael Bergqvist ◽  
Malin Wickström ◽  
Peter Ericsson ◽  
Linda Sooman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Vitro Activity ◽  
Insulin Like Growth Factor ◽  
In Vitro Activity ◽  
Lung Cancer Cell

Effect of insulin-like growth factor 1 receptor inhibitor on sensitization of head and neck cancer cells to cetuximab and methotrexate

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6079-6079
Author(s):  
H. Hatakeyama ◽  
J. Parker ◽  
D. Wheeler ◽  
P. Harari ◽  
S. Levy ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Head And Neck ◽  
Cell Lines ◽  
Radiation Resistance ◽  
Chemotherapeutic Agents ◽  
Insulin Like Growth Factor ◽  
Igf1r Inhibitor

6079 Background: Insulin-like growth factor 1 receptor (IGF1R) is highly expressed in head and neck squamous cell carcinoma (HNSCC) and IGF1R inhibitors have been shown to modulate sensitivity to selected chemotherapeutic agents and radiation. The combination effects of an IGF1R inhibitor, MK-0646, with cetuximab or cytotoxic agents that are commonly used in the treatment of recurrent and/or metastatic HNSCC were examined in cetuximab resistant and sensitive HNSCC cell lines. Methods: The cell lines, SCC1 and its cetuximab-resistant clone 1Cc8, were treated with MK-0646, cetuximab or methotrexate, and a combination of MK-0646 and each anti-cancer drug (MK-0646 was supplied by Merck & Co., Inc.). The effect of treatments on cell proliferation and anti-tumor activity was determined using MTS assay in vitro and in vivo using mouse xenografts generated from the cell lines. Overall changes in the gene and protein expressions with the treatments were determined by DNA microarrays and western blots. Results: The IGF1R inhibitor, MK-0646, showed high-sensitivity in vitro xenograft model in SCC1 as monotherapy and increased sensitivity to cetuximab in SCC1 and to methotrexate in 1Cc8 in combination. However, MK-0646 did not inhibit cell proliferation in vitro and in vivo in 1Cc8. The gene expression array and western blot analyses showed that MK-0646 decreased expression of AKT and dihydrofolate reductase (DHFR), a target of methotrexate. Increased expressions of AKT and DHFR have been shown to associate with cetuximab and methotrexate resistance as well as radiation resistance. Conclusions: The development of tolerance in response to the IGF1R inhibitor and cetuximab is common. Whereas IGF1R inhibitors may have little therapeutic impact in cetuximab resistant, the IGF1R inhibitor may modulate response to selected chemotherapeutic agents and to radiation. The IGF1R inhibitor appears to enhance cetuximab and methotrexate response, and modulates genes associated with radiation resistance thereby providing alternative regimens for recurrent and refractory HNSCC patients who have developed resistance to initial therapies. No significant financial relationships to disclose.

scholarly journals Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma

Blood ◽  
2012 ◽  
Vol 120 (16) ◽  
pp. 3260-3270 ◽  
Author(s):  
Deborah J. Kuhn ◽  
Zuzana Berkova ◽  
Richard J. Jones ◽  
Richard Woessner ◽  
Chad C. Bjorklund ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Cell Lines ◽  
Proteasome Inhibition ◽  
Myeloma Cell ◽  
Resistant Cell ◽  
In Vivo Model ◽  
Insulin Like Growth Factor

Abstract Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)–1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA–mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bor-tezomib. Importantly, OSI-906 in combination with bortezomib also overcame bor-tezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.

scholarly journals Heterogeneity of neuroblastoma cell lines in insulin-like growth factor 1 receptor/Akt pathway-mediated cell proliferative responses

2013 ◽  
Vol 104 (9) ◽  
pp. 1162-1171 ◽  
Author(s):  
Lei Qi ◽  
Hidemi Toyoda ◽  
Vipin Shankar ◽  
Naoto Sakurai ◽  
Keishirou Amano ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Akt Pathway ◽  
Insulin Like Growth Factor ◽  
Neuroblastoma Cell Lines
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