In vivo analysis of insulin-like growth factor type 1 receptor humanized monoclonal antibody MK-0646 and small molecule kinase inhibitor OSI-906 in colorectal cancer

Leiphrakpam, Premila D.; Agarwal, Ekta; Mathiesen, Michelle R.; Haferbier, Katie L; Brattain, Michael G.; Chowdhury, Shantanu

doi:10.3892/or.2013.2819

Cited by 27 publications

(37 citation statements)

References 45 publications

(61 reference statements)

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“…From a clinical point of view, increased expression of IGF1R in response to in vitro and in vivo exposure to trabectedin, provides the rationale for a combined use of trabectedin with anti-IGF1R agents. Here, we demonstrate the advantages of this combination either using HAb AVE1642, a well-tolerated agent that binds human IGF1R specifically and with high affinity (45,46), or the dual inhibitor IGF1R/IR, OSI-906, a small molecule shown to have antitumoral activity against several tumors (47,48), including osteosarcoma (49). The association of OSI-906 with trabectedin gave synergistic effects in all of the 13 EWS cell lines here considered, including cells resistant to trabectedin (18) or to anti-IGF1R agents (29).…”

Section: Discussionmentioning

confidence: 99%

“…This appears to be due mainly to the complementary proapoptotic effects of the two drugs that by affecting different pathways give rise to a combination able to deliver cell death messages in all EWS cells, independently from the p53 status. Although treatment with IGF1R antagonists is known to lead to downregulation of the proteins involved in cell survival and inhibition of cell death (38,47), thereby recovering cell sensitivity to apoptosis, trabectedin has been previously described as a potent DNA-damaging agent. Trabectedin binds to guanines in the minor groove with some degree of sequence specificity, inducing SSB that rapidly turn into DSB, the most lethal form of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

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Trabectedin Efficacy in Ewing Sarcoma Is Greatly Increased by Combination with Anti-IGF Signaling Agents

Amaral

Garofalo

Frapolli

et al. 2015

Clinical Cancer Research

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Purpose: Goal of this study was to identify mechanisms that limit efficacy of trabectedin (ET-743, Yondelis) in Ewing sarcoma (EWS), so as to develop a clinical applicable combination therapy. Experimental Design: By chromatin immunoprecipitation, we analyzed EWS–FLI1 binding to the promoters of several target genes, such as TGFβR2, CD99, insulin-like growth factor receptor 1 (IGF1R), and IGF1, both in vitro and in xenografts treated with trabectedin or doxorubicin. Combined therapy with trabectedin and anti-IGF1R agents (AVE1642 HAb; OSI-906) was tested in vitro and in xenografts. Results: We confirm that both trabectedin and doxorubicin were able to strongly reduce EWS–FLI1 (both type I and type II) binding to two representative target genes (TGFβR2 and CD99), both in vitro and in xenografts. However, trabectedin, but not doxorubicin, was also able to increase the occupancy of EWS–FLI1 to IGF1R promoters, leading to IGF1R upregulation. Inhibition of IGF1R either by the specific AVE1642 human antibody or by the dual IGF1R/insulin receptor inhibitor OSI-906 (Linsitinib) greatly potentiate the efficacy of trabectedin in the 13 EWS cell lines here considered as well as in TC-71 and 6647 xenografts. Combined therapy induced synergistic cytotoxic effects. Trabectedin and OSI-906 deliver complementary messages that likely converge on DNA-damage response and repair pathways. Conclusions: We showed that trabectedin may not only inhibit but also enhance the binding of EWS–FLI1 to certain target genes, leading to upregulation of IGF1R. We here provide the rationale for combining trabectedin to anti-IGF1R inhibitors. Clin Cancer Res; 21(6); 1373–82. ©2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Trabectedin Efficacy in Ewing Sarcoma Is Greatly Increased by Combination with Anti-IGF Signaling Agents

Amaral

Garofalo

Frapolli

et al. 2015

Clinical Cancer Research

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“…Phosphorylation of ezrin at T567 leads to PKA activation and cell survival IGF1R signaling plays an important role in colon cancer cell survival (36,37). Whereas its inhibition leads to downregulation of XIAP and survivin and induction of apoptosis (36), its activation by transferrin and insulin (TI) increases cell survival (37).…”

Section: Tgfβ Inhibits Ezrin Phosphorylation At T567 Resulting In Pkamentioning

confidence: 99%

“…Whereas its inhibition leads to downregulation of XIAP and survivin and induction of apoptosis (36), its activation by transferrin and insulin (TI) increases cell survival (37). We have previously shown that inhibition of IGF1R decreases ezrin phosphorylation at T567 (5), indicating that IGF1R-mediated signaling activates ezrin by increasing T567 phosphorylation.…”

Section: Tgfβ Inhibits Ezrin Phosphorylation At T567 Resulting In Pkamentioning

confidence: 99%

TGFβ and IGF1R signaling activates protein kinase A through differential regulation of ezrin phosphorylation in colon cancer cells

Leiphrakpam

Brattain

Black

et al. 2018

Journal of Biological Chemistry

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Aberrant cell survival plays a critical role in cancer progression and metastasis. We have previously shown that ezrin, a cAMP-dependent A-kinase anchoring protein (AKAP), is upregulated in colorectal cancer (CRC) liver metastasis. Phosphorylation of ezrin at threonine 567(T567) activates ezrin and plays an important role in CRC cell survival associated with XIAP and survivin upregulation. In this study, we demonstrate that, in FET and GEO colon cancer cells, knockdown of ezrin expression or inhibition of ezrin phosphorylation at T567 increases apoptosis through PKA activation in a cAMPindependent manner. TGFβ signaling inhibits ezrin phosphorylation in a Smad3-dependent and Smad2-independent manner and regulates proapoptotic function through ezrin-mediated PKA activation. On the other hand, ezrin phosphorylation at T567 by IGF1R signaling leads to cAMP-dependent PKA activation and enhances cell survival. Further studies indicate that phosphorylated ezrin forms a complex with PKA RII and dephosphorylated ezrin dissociates from the complex and facilitates the association of PKA RII with AKAP149, both of which activate PKA yet lead to either cell survival or apoptosis. Thus, our studies reveal a novel mechanism of differential PKA activation mediated by TGFβ and IGF1R signaling through regulation of ezrin phosphorylation in CRC resulting in different cell fate. This is of significance because TGFβ and IGF1R signaling pathways are well characterized tumor suppressor and oncogenic pathways respectively with important roles in CRC tumorigenesis and metastasis. Our studies indicate that they crosstalk and antagonize each other's function through regulation of ezrin activation. Therefore, ezrin may be a potential therapeutic target in CRC.

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“…OSI-906 showed anti-proliferative effects in several colorectal cancer (CRC) and non-small-cell lung cancer tumor cell lines3435 and inhibited tumor growth in different xenograft mouse models343637. Anti-tumor activities have been reported in phase I clinical trials with colorectal cancer and adrenocortical carcinoma3839.…”

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confidence: 99%

Insulin-IGF signaling affects cell transformation in the BALB/c 3T3 cell model

Poburski

Leovsky

Boerner

et al. 2016

Sci Rep

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The increased cancer mortality of diabetes type 2 patients is most likely an evidence of the tight connection between tumor development and energy metabolism. A major focus of today’s research is still the identification of key proteins of both diseases and the development of corresponding inhibitors. In this study we combined the two-stage BALB/c-3T3 cell transformation assay (BALB-CTA) with the IR/IGF-1R inhibitor OSI-906 (linsitinib) and analyzed alterations in protein activity and energy parameters in non-transformed as well as transformed cells. OSI-906 successfully inhibited the phosphorylation of IR/IGF-1R and decreased cell growth in non-transformed cells. In the BALB-CTA, a permanent treatment with OSI-906 reduced cellular transformation dose-dependently, whereas a temporary treatment gave evidence for a preventive effect in the promotion phase. Furthermore, even though several key proteins were affected, it was possible to show that the phosphorylation of GSK3, Erk 1/2 and the S6 protein are not crucial for the cell foci reducing effect of OSI-906. Taken together, the BALB-CTA confirmed results of OSI-906 from animal studies and enhanced the knowledge of its mode of action. Therefore, the BALB-CTA offers the opportunity to analyze alterations in the transformation process more precisely and will be helpful to identify effective cancer treatments.

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In vivo analysis of insulin-like growth factor type 1 receptor humanized monoclonal antibody MK-0646 and small molecule kinase inhibitor OSI-906 in colorectal cancer

Cited by 27 publications

References 45 publications

Trabectedin Efficacy in Ewing Sarcoma Is Greatly Increased by Combination with Anti-IGF Signaling Agents

Trabectedin Efficacy in Ewing Sarcoma Is Greatly Increased by Combination with Anti-IGF Signaling Agents

TGFβ and IGF1R signaling activates protein kinase A through differential regulation of ezrin phosphorylation in colon cancer cells

Insulin-IGF signaling affects cell transformation in the BALB/c 3T3 cell model

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