Predictive factors of response to mTOR inhibitors in neuroendocrine tumours

Zatelli, Maria Chiara; Fanciulli, Giuseppe; Malandrino, Pasqualino; Ramundo, Valeria; Faggiano, Antongiulio; Colao, Annamaria

doi:10.1530/erc-15-0413

Cited by 30 publications

(25 citation statements)

References 93 publications

(89 reference statements)

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“…The PI3K/AKT/mTOR pathway is constitutively activated in different NETs, including those of pancreatic origin . The expression of mTOR pathway components has been suggested to correlate with clinical behavior and responsiveness to mTOR inhibitors (Righi et al 2010, Qian et al 2013, Zatelli et al 2016. The mTOR inhibitor has recently shown antitumor activity in advanced, well-differentiated and moderately differentiated P-NETs , but resistance to this treatment may develop.…”

Section: :11mentioning

confidence: 99%

“…We recently demonstrated that responsiveness to Everolimus in human bronchial carcinoid primary cultures correlates with an active AKT/mTOR signaling pathway (Gagliano et al 2013). However, PI3K/AKT/mTOR signaling does not always predict the sensitivity to mTOR inhibitors and is difficult to assess (Zatelli et al 2016). Therefore, the aim of this study was to investigate the possible predictors of sensitivity to Everolimus in P-NET, to identify patients who may benefit from treatment avoiding useless side effects in resistant patients.…”

Section: :11mentioning

confidence: 99%

“…The latter represents a relevant issue because previous evidence demonstrated that some patients do not benefit from Everolimus treatment, due to the development of primary or secondary acquired resistance to this drug (Fazio 2015), despite a significant prolongation of PFS shown by the RADIANT-3 trial in a significant number of patients with P-NET . However, the precise mechanism underlying Everolimus resistance remains unknown (Zatelli et al 2016).…”

Section: Figurementioning

confidence: 99%

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mTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors

Falletta¹,

Partelli²,

Rubini³

et al. 2016

Endocrine-Related Cancer

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Medical therapy of pancreatic neuroendocrine tumors (P-NET) may take advantage of Everolimus treatment. However, the extent of therapeutic response cannot be predicted. This study was aimed to identify the possible predictive markers of response to Everolimus in P-NET. We found that Everolimus reduced the cell viability and induced apoptosis in primary cultures of 6 P-NET (P-NET-R), where the proliferative and antiapoptotic effects of IGF1 were blocked by Everolimus. On the contrary, 14 P-NET primary cultures (P-NET-NR) were resistant to Everolimus and IGF1, suggesting an involvement of PI3K/AKT/mTOR pathway in the mechanism of resistance. The response to Everolimus in vitro was associated with an active AKT/mTOR pathway and seemed to be associated with a greater clinical aggressiveness. In addition, a patient sensitive to Everolimus in vitro was sensitive to this drug in vivo also and showed a positive p-AKT immunohistochemistry (IHC) at tissue level. Similarly, a patient resistant to Everolimus treatment after surgery was not sensitive to the drug in vitro and had a negative p-AKT IHC staining. Therefore, present data confirm that P-NET primary cultures may be considered a model for testing medical treatment efficacy and that IHC characterization of p-AKT might help in identifying human P-NET who can benefit from Everolimus treatment. These data encourage conducting a prospective multicenter study involving different groups of P-NET patients treated with Everolimus.

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Section: :11mentioning

confidence: 99%

Section: :11mentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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mTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors

Falletta¹,

Partelli²,

Rubini³

et al. 2016

Endocrine-Related Cancer

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“…Several studies investigated the role of various predictors of response to mTOR inhibitors, including clinical, biological, and histological factors (Zatelli et al 2016).…”

Section: Predictive Factors Of Response To Everolimusmentioning

confidence: 99%

Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives

Gallo

Malandrino

Fanciulli

et al. 2017

J Cancer Res Clin Oncol

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Results We identified eight retrospective published studies, two prospective published studies, and five registered clinical trials. Moreover, we analyzed the content of four widespread international guidelines. Conclusions Our critical review confirms the lack of highquality data to recommend everolimus as the first line therapy for pNETs. The ongoing clinical trials reported in this review will hopefully help clinicians, in the near future, to better evaluate the role of everolimus as the first line therapy for pNETs. However, at the moment, there is already enough evidence to recommend everolimus as the first line therapy for patients with symptomatic malignant unresectable insulin-secreting pNETs, to control the endocrine syndrome regardless of tumour growth.

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“…It is therefore not surprising that somatostatin analogs (SSAs) are active in the treatment of a broad spectrum of NETs [5]. Likewise, the mammalian target of rapamycin (mTOR) pathway is upregulated in a large percentage of NETs regardless of primary site, even though mutations in the mTOR pathway are observed almost exclusively in pancreatic NETs [6]. Indeed, recent clinical trials demonstrate that mTOR inhibition is an appropriate strategy for treatment of both pancreatic and nonpancreatic NETs [7,8 && ].…”

Section: Introductionmentioning

confidence: 99%