455 Role of MDM2 as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs)

Briest, Franziska; Grass, Irina; Christen, Friederike; Lewens, Florentine; Freitag, Helma; Kaemmerer, Daniel; Saenger, J.; Hummel, Margit; Siegmund, Britta; Grabowski, Patricia

doi:10.1016/s0959-8049(14)70581-7

Cited by 3 publications

(9 citation statements)

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“…wild type KRJ-1 cells [18,19] , indicate that p53 wild type expression is essential for the sensitivity of NET cells to MDM2 inhibition. In a sequence analysis of exons 4-10 of TP53, only GOT1 cells showed no mutations in the TP53 gene.…”

Section: Discussionmentioning

confidence: 99%

“…Another human NET cell line, KRJ-1, has also been reported to harbor a nonmutated TP53 gene and to be sensitive to treatment with the MDM2 inhibitor nutlin-3 [18,19] . Thus, the human NET cell lines GOT1 and KRJ-1 expressing p53 wild type seem valid models for the future evaluation of p53-mediated treatment strategies in NETs.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, NETs harbor copy number gains in the endogenous p53 inhibitors MDM2 in 20%, MDM4 in 30%, and WIP1 in 51% of the cases [20] . Thus, inhibiting MDM2 and increasing the expression of p53 wild type in these tumors might be a promising target for patients with NETs [18,19] and should be evaluated in further preclinical studies and clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…MDM2 inhibition has recently been discussed as a potential treatment strategy in NETs due to several circumstances [18,19] . NETs frequently overexpress p53 inhibitors, as copy number gains in MDM2, MDM4, and p53 wild type -induced phosphatase 1 (WIP1) have been found in NETs of pancreatic origin in 22,30, and 51% of the cases, respectively [20] .…”

Section: Introductionmentioning

confidence: 99%

“…Currently, there are only preliminary preclinical data regarding the effects of MDM2 inhibitors on NET cell lines [18,19] . Therefore, we aimed to investigate in vitro the effects of the MDM2 inhibitor NVP-CGM097 (Novartis) on human NET cells of small intestinal (GOT1), pancreatic (BON1), and bronchial (NCI-H727) origin.…”

Section: Introductionmentioning

confidence: 99%

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The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

et al. 2016

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Background/Aims: The tumor suppressor p53 is depleted in many tumor cells by the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2) through MDM2/p53 interaction. A novel target for inhibiting p53 degradation and for causing reexpression of p53^{wild type} is inhibition of MDM2. The small molecule NVP-CGM097 is a novel MDM2 inhibitor. We investigated MDM2 inhibition as a target in neuroendocrine tumor cells in vitro. Methods: Human neuroendocrine tumor cell lines from the pancreas (BON1), lung (NCI-H727), and midgut (GOT1) were incubated with the MDM2 inhibitor NVP-CGM097 (Novartis) at concentrations from 4 to 2,500 nM. Results: While p53^{wild type} GOT1 cells were sensitive to NVP-CGM097, p53^mutated BON1 and p53^mutated NCI-H727 cells were resistant to NVP-CGM097. Incubation of GOT1 cells with NVP-CGM097 at 100, 500, and 2,500 nM for 96 h caused a significant decline in cell viability to 84.9 ± 9.2% (p < 0.05), 77.4 ± 6.6% (p < 0.01), and 47.7 ± 9.2% (p < 0.01). In a Western blot analysis of GOT1 cells, NVP-CGM097 caused a dose-dependent increase in the expression of p53 and p21 tumor suppressor proteins and a decrease in phospho-Rb and E2F1. Experiments of co-incubation of NVP-CGM097 with 5-fluorouracil, temozolomide, or everolimus each showed additive antiproliferative effects in GOT1 cells. NVP-CGM097 and 5-fluorouracil increased p53 and p21 expression in an additive manner. Conclusions: MDM2 inhibition seems a promising novel therapeutic target in neuroendocrine tumors harboring p53^{wild type}. Further investigations should examine the potential role of MDM2 inhibitors in neuroendocrine tumor treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

et al. 2016

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The p53 network as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms

Briest

Grabowski

2015

Cancer Treatment Reviews

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Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets

Prada

Auernhammer

2018

Endocrine Connections

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Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression-free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras–Raf–MEK–ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors.

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455 Role of MDM2 as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs)

Cited by 3 publications

References 0 publications

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

The p53 network as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms

Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets

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