The insulin-like growth factor 1 pathway is a potential therapeutic target for low-grade serous ovarian carcinoma

King, Erin R.; Zu, Zhifei; Tsang, Yvonne T.M.; Deavers, Michael T.; Malpica, Anaís; Mok, Samuel C.; Gershenson, David M.; Wong, Kwong-Kwok

doi:10.1016/j.ygyno.2011.06.016

Cited by 51 publications

(44 citation statements)

References 30 publications

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“…Tissue culture and xenograft studies have confirmed the antitumor properties of OSI-906 in several types of human cancer cells, including lung (13), colon (14, 15), liver (16), and ovarian (17). However, like other receptor tyrosine kinases that have been tested as therapeutic targets, tumor cells frequently develop resistance to IGF-1R inhibitors.…”

Section: Introductionmentioning

confidence: 90%

Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells

Zhang

Wang

Chen

et al. 2015

Molecular Cancer Therapeutics

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Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single agent targeting IGF-1R, attempts in later studies failed due to resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor, OSI-906, in colorectal cancer (CRC) cells and the mechanism underlying this impact. Using OSI-906 resistant and sensitive CRC cells, we found that the Pdcd4 level directly correlates with cell chemosensitivity to OSI-906. In addition, tumors derived from Pdcd4 knockdown cells resist the growth inhibitory effect of OSI-906 in a CRC xenograft mouse model. Moreover, Pdcd4 enhances the antiproliferative effect of OSI-906 in resistant cells through suppression of p70S6K1 activation. Knockdown of p70S6K1, but not p70S6K2, significantly increases the chemosensitivity of OSI-906 in cultured CRC cells. Furthermore, the combination of OSI-906 and PF4708671, a p70S6K1 inhibitor, efficiently suppresses the growth of OSI-906 resistant colon tumor cells in vitro and in vivo. Taken together, activation of p70S6K1 that is inhibited by Pdcd4 is essential for resistance to IGF-1R inhibitor in colon tumor cells, and the combinational treatment of OSI-906 and PF-4708671 results in enhanced antiproliferation effects in CRC cells in vitro and in vivo, providing a novel venue to overcome the resistance to IGF-1R inhibitor in treating colorectal cancer.

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Section: Introductionmentioning

confidence: 90%

Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells

Zhang

Wang

Chen

et al. 2015

Molecular Cancer Therapeutics

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“…The HOC-7 cell line was derived from the malignant ascite of a patient with stage III low-grade adenocarcinoma of the ovary (28,29) and contains wild-type TP53 as determined by sequencing. OSE cells were isolated and cultured as previously described (8).…”

Section: Cell Lines and Isolation And Culture Of Primary Ose Cellsmentioning

confidence: 99%

Wild-Type Tumor Repressor Protein 53 (TRP53) Promotes Ovarian Cancer Cell Survival

et al. 2012

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Loss of Pten in the Kras(G12D);Amhr2-Cre mutant mice leads to the transformation of ovarian surface epithelial (OSE) cells and rapid development of low-grade, invasive serous adenocarcinomas. Tumors occur with 100% penetrance and express elevated levels of wild-type tumor repressor protein 53 (TRP53). To test the functions of TRP53 in the Pten;Kras (Trp53+) mice, we disrupted the Trp53 gene yielding Pten;Kras(Trp53-) mice. By comparing morphology and gene expression profiles in the Trp53+ and Trp53- OSE cells from these mice, we document that wild-type TRP53 acts as a major promoter of OSE cell survival and differentiation: cells lacking Trp53 are transformed yet are less adherent, migratory, and invasive and exhibit a gene expression profile more like normal OSE cells. These results provide a new paradigm: wild-type TRP53 does not preferentially induce apoptotic or senescent related genes in the Pten;Kras(Trp53+) cancer cells but rather increases genes regulating DNA repair, cell cycle progression, and proliferation and decreases putative tumor suppressor genes. However, if TRP53 activity is forced higher by exposure to nutlin-3a (a mouse double minute-2 antagonist), TRP53 suppresses DNA repair genes and induces the expression of genes that control cell cycle arrest and apoptosis. Thus, in the Pten;Kras(Trp53+) mutant mouse OSE cells and likely in human TP53+ low-grade ovarian cancer cells, wild-type TRP53 controls global molecular changes that are dependent on its activation status. These results suggest that activation of TP53 may provide a promising new therapy for managing low-grade ovarian cancer and other cancers in humans in which wild-type TP53 is expressed.

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“…A randomized phase II trial of the MEK inhibitor AZD6244 and an AKT inhibitor (MK2206) is planned. As low-grade ovarian cancers express IGFR, studies are also being undertaken with a humanized anti-IGFR antibody [25].…”

Section: Hereditary and Sporadicmentioning

confidence: 99%

Molecular approaches to personalizing management of ovarian cancer

Bast

2011

Annals of Oncology

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Cytoreductive surgery and empirical combination chemotherapy have improved 5-year survival for ovarian cancer patients, but have not increased the overall rate of cure. Poor outcomes relate, at least in part, to late diagnosis and to the persistence of dormant ovarian cancer cells that have resisted conventional drugs. Increased understanding of the molecular, cellular and clinical biology of ovarian cancer must be translated into personalized therapy with conventional and targeted agents as well as personalized detection of high-grade cancers in early stages. Different strategies will be required to treat low-grade and high-grade serous cancers as well as other histotypes. Activating mutations of Ras and Raf can be targeted in low-grade cancers. Activation of the PI3K pathway-PI3Kness-and inactivation of BRCA function-BRCAness-can be targeted in high-grade lesions. Inhibition of multiple pathways will be required. Sensitivity of primary cancers to paclitaxel and platinum can be modulated by inhibiting kinases and other molecules that regulate the cell cycle. Dormant ovarian cancer cells may depend upon autophagy, cytokines and growth factors for survival. Early detection can utilize two stage strategies where rising serum biomarker levels prompt imaging in a small fraction of women. Screening can be personalized by taking into account each woman's baseline biomarker levels.

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The insulin-like growth factor 1 pathway is a potential therapeutic target for low-grade serous ovarian carcinoma

Cited by 51 publications

References 30 publications

Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells

Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells

Wild-Type Tumor Repressor Protein 53 (TRP53) Promotes Ovarian Cancer Cell Survival

Molecular approaches to personalizing management of ovarian cancer

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