Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors

Moreno, Amy C.; Akçakanat, Argun; Munsell, Mark F.; Soni, Alpana; Yao, James C.; Meric‐Bernstam, Funda

doi:10.1677/erc-07-0202

Cited by 136 publications

(109 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The notion that this pathway is of importance in this tumour entity has further been substantiated by results of a highthroughput RNA expression analysis of pancreatic NETs in which the upstream inhibitors of mTOR, TSC2 and PTEN were found to be downregulated (Missiaglia et al 2010). In addition, mTOR inhibition by rapamycin has been shown to significantly reduce NETs cell growth in vitro and in vivo (Moreno et al 2008). This might be due to an induction of growth arrest in G 0 /G 1 phase and enhanced apoptosis (Zitzmann et al 2007).…”

Section: Discussionmentioning

confidence: 96%

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Kasajima¹,

Pavel²,

Darb‐Esfahani³

et al. 2010

Endocrine Related Cancer

View full text Add to dashboard Cite

Clinical trials indicate efficacy of drugs inhibiting the mammalian target of rapamycin (mTOR) in the treatment of gastroenteropancreatic neuroendocrine tumours (GEP-NET); however, information on detailed expression and activity patterns of mTOR in these tumours is sparse. We investigated the expression of mTOR and expression as well as phosphorylation of its downstream targets 4EBP1, S6K and eIF4E in a cohort of 99 human GEP-NET by immunohistochemistry. We correlated our findings with clinicopathological variables and patient prognosis. We found that 61, 93, 80, 69, 57 and 79% of GEP-NET were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1), nuclear p-4EBP1, phospho-S6K (p-S6K) and phospho-eIF4E (p-eIF4E) respectively. mTOR expression and activity were higher in foregut than in midgut tumours. In foregut tumours, expression of mTOR was higher when distant metastases were present (PZ0.035). Strong mTOR activity was associated with higher proliferative capacity. In patients with stage IV midgut tumours, strong p-S6K expression was associated with poor disease-specific survival (PZ0.048). In conclusion, mTOR shows considerable variations in expression and activity patterns in GEP-NET in dependence of tumour location and metastatic status. We hypothesise that these differences in mTOR expression and activity might possibly influence response to mTOR inhibitors.

show abstract

Section: Discussionmentioning

confidence: 96%

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Kasajima¹,

Pavel²,

Darb‐Esfahani³

et al. 2010

Endocrine Related Cancer

View full text Add to dashboard Cite

show abstract

“…Chemotherapyinduced activation of Akt has been reported to confer resistance to treatment in some cellular systems (Huang & Hung 2009). However, this appears to be a complex system as recently in two NET cell lines treated with the mammalian target of rapamycin (mTOR) inhibitor rapamycin; Akt was found to be induced despite significant inhibition of cellular proliferation (Moreno et al 2008). When analysis was restricted to systemic chemotherapy alone, lack of Akt expression remained correlated with response to doxorubicin.…”

Section: Discussionmentioning

confidence: 97%

Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors

O’Toole¹,

Couvelard²,

Rebours³

et al. 2010

Endocrine-Related Cancer

View full text Add to dashboard Cite

Response rates to cytotoxics in gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) vary; recent trials demonstrated lack of objective response rates in up to 70% of patients. Identification of predictive therapeutic biomarkers would be beneficial in the treatment of GEP. Selected markers with known or suspected capability of predicting response to cytotoxics or prognosis (Ki-67, p53, multidrug resistance protein-1 (MDR1), Akt, thymidylate synthase (TS), phosphatase and tensin homolog (PTEN), CA9, cluster of differentiation 34 (CD34), vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1, mismatch repair gene -human mutL homolog 1 (hLMH1), and Bcl-2) were analyzed using immunohistochemisrtry in 60 treatment-naive patients receiving chemotherapy (nZ46) or chemoembolization (nZ14) for inoperable advanced and/or metastatic GEP and correlated with prognosis (survival and response rates). Therapy included systemic chemotherapy with streptozotocin (nZ28), doxorubicin (nZ14), 5-fluorouracil (nZ18), and etoposide/cisplatinum (nZ16), or chemoembolization (streptozotocin, 9; doxorubicin, 5). Factors associated with overall survival in the entire cohort were Ki-67, P!0.001; tumor grade, P!0.001; tumor differentiation, P!0.001; CA9, PZ0.004; Akt, PZ0.01; HIF-1, P!0.001; p53, P!0.0001; and hMLH1, PZ0.005. Markers associated with treatment response included overall group: Akt and PTEN (PZ0.05 and 0.05 respectively); streptozotocin: Akt (PZ0.07), TS (PZ0.02), and PTEN (PZ0.017); doxorubicin: Ki-67 (PZ0.05), Akt (PZ0.06), and CA9 (PZ0.02). At multivariate analysis, Akt was significantly associated with a nonresponse to therapy (objective response (OR): 0.2 (0.05-0.8)). For patients receiving only systemic chemotherapy (nZ46), PTEN (0.04) and hLMH1 (0.03) were correlated with treatment response and for individual molecules were streptozotocin: PTEN (PZ0.008) and hLMH1 (0.07); doxorubicin: Akt (PZ0.09), CA9 (PZ0.09), and hLMH1 (PZ0.09). These results demonstrate a number of new prognostic biomarkers in GEP-NET, and in addition, response to chemotherapy was correlated with a simple panel of selected markers (such as CA9, Akt, PTEN, TS, and hLMH1).

show abstract

“…So far, only a few preclinical reports, mainly based on in vitro experiments, have appeared. [5][6][7][8] In this context, the objective of our study was to evaluate, in vitro and in vivo, the effects of rapamycin on intestinal endocrine tumor cell lines, representative of the human highgrade endocrine carcinomas that are putative targets for treatment by rapamycin analogues. 19 Our results suggest that rapamycin may act through several coordinated mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Targeting the PI3K/mTOR pathway upstream of Akt thus appeared to be a promising strategy to improve the effects of mTOR inhibitors: this lends further support to the use of PI3K inhibitors that are currently in clinical trials. 26 Preclinical studies with rapamycin or its analogues have usually been performed only in vitro, except for the work by Moreno et al 6 These authors used a subcutaneous xenograft model to demonstrate a significant decrease in tumor size in mice treated with rapamycin for 30 days. However, the subcutaneous model has little physiopathologic relevance.…”

Section: Discussionmentioning

confidence: 99%

“…Only four recent works reported on the effects of rapamycin or its analog RAD001 on endocrine cell lines on the basis of in vitro experiments. [5][6][7][8] To gain further insight into the mechanisms of antitumor activity of rapalogues in GEP neuroendocrine tumors, we designed an experimental study based on two murine endocrine cell lines, STC-1 and GLUTag, which mimic the behavior of human high-grade endocrine carcinoma. After establishing the in vitro effects of rapamycin, we attempted to evaluate in vivo, using a preclinical animal model of intrahepatic dissemination developed in the laboratory, 9 the relative contributions of the antiproliferative, proapoptotic, and antiangiogenic effects that may be exerted by rapamycin alone or in combination with the PI3K inhibitor LY294002, which targets the same pathway.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Targeting the PI3K/mTOR Pathway in Murine Endocrine Cell Lines

Couderc

Poncet

Villaume

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

The mammalian target of rapamycin (mTOR) inhibitors, such as rapalogues, are a promising new tool for the treatment of metastatic gastroenteropancreatic endocrine tumors. However, their mechanisms of action remain to be established. We used two murine intestinal endocrine tumoral cell lines, STC-1 and GLUTag, to evaluate the antitumor effects of rapamycin in vitro and in vivo in a preclinical model of liver endocrine metastases. In vitro, rapamycin inhibited the proliferation of cells in the basal state and after stimulation by insulin-like growth factor-1. Simultaneously, p70S6 kinase and 4EBP1 phosphorylation was inhibited. In vivo, rapamycin substantially inhibited the intrahepatic growth of STC-1 cells, irrespectively of the timing of its administration and even when the treatment was administered after cell intrahepatic engraftment. In addition, treated animals had significantly prolonged survival (mean survival time: 47.7 days in treated animals versus 31.8 days in controls) and better clinical status. Rapamycin treatment was associated with a significant decrease in mitotic index and in intratumoral vascular density within STC-1 tumors. Furthermore, the antitumoral effect obtained after treatment with a combination of rapamycin and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was more significant than with rapamycin alone in both cell lines. Our results suggest that the antitumor efficacy of rapamycin in neuroendocrine tumors results from a combination of antiproliferative and antiangiogenic effects. Interestingly, a more potent antitumor efficiency could be obtained by simultaneously targeting several levels of the PI3K/ mTOR pathway.

show abstract

Antitumor activity of rapamycin and octreotide as single agents or in combination in neuroendocrine tumors

Cited by 136 publications

References 28 publications

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors

Targeting the PI3K/mTOR Pathway in Murine Endocrine Cell Lines

Contact Info

Product

Resources

About