Publication Name	World Journal of Clinical Oncology
Manuscript ID	21154
Country	Italy

Received	2015-06-29 15:46
Peer-Review Started	2015-07-03 15:54
To Make the First Decision	2015-07-27 15:55
Return for Revision	2015-07-30 19:18
Revised	2015-09-07 00:00
Second Decision	2015-09-14 10:21
Accepted by Journal Editor-in-Chief
Accepted by Company Editor-in-Chief	2015-09-28 17:33
Articles in Press	2015-09-28 17:33
Publication Fee Transferred
Edit the Manuscript by Language Editor
Typeset the Manuscript	2015-11-30 11:53
Publish the Manuscript Online	2015-12-09 18:37

ISSN	2218-4333 (online)
Open Access	This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
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Category	Oncology
Manuscript Type	Editorial
Article Title	Neuroendocrine tumors resistant to mammalian target of rapamycin inhibitors: A difficult conversion from biology to the clinic
Manuscript Source	Invited Manuscript
All Author List	Nicola Fazio
Funding Agency and Grant Number
Corresponding Author	Nicola Fazio, MD, PhD, Unit of Gastroin­testinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Via Ripamonti, 43, 20141 Milan, Italy. nicola.fazio@ieo.it
Key Words	Everolimus; BEZ235; Mammalian target of rapamycin; Phosphoinositide 3-kinase; Mammalian target of rapamycin C; Resistance; Mammalian target of rapamycin inhibitor
Core Tip	Although everolimus significantly prolongs progression-free survival in patients with advanced pancreatic neuroendocrine tumors (NETs), some patients are refractory or progress early after an initial response. Mammalian target of rapamycin (mTOR) C2 and insulin growth factor (IGF) - IGF receptor signaling can mediate two supposed mechanisms of resistance to everolimus. BEZ235 is a multitargeted inhibitor binding to phosphoinositide 3-kinase, mTORC1 and mTORC2, therefore potentially turning off all the supposed mole-cular targets of resistance to everolimus. The two clinical trials designed in pancreatic NETs were stopped early due to unmet statistical endpoint and the global clinical development of BEZ235 was halted. Challenging tolerability probably conditioned the results. The BEZ experience is an example of the huge difference between preclinical and clinical setting and prompts us to pay more attention to the phase?Ⅰ?step of clinical development and the design of higher-phase trials.
Publish Date	2015-12-09 18:37
Citation	Fazio N. Neuroendocrine tumors resistant to mammalian target of rapamycin inhibitors: A difficult conversion from biology to the clinic. World J Clin Oncol 2015; 6(6): 194-197
URL	http://www.wjgnet.com/2218-4333/full/v6/i6/194.htm
DOI	http://dx.doi.org/10.5306/wjco.v6.i6.194

Full Article (PDF)	WJCO-6-194.pdf
Full Article (Word)	WJCO-6-194.doc
Manuscript File	21154-Review.docx
Answering Reviewers	21154-Answering reviewers.pdf
Audio Core Tip	21154-Audio core tip.mp3
Conflict-of-Interest Disclosure Form	21154-Conflict-of-interest statement.pdf
Copyright License Agreement	21154-Copyright assignment.pdf
Non-Native Speakers of English Editing Certificate	21154-Language certificate.pdf
Peer-review Report	21154-Peer-review(s).pdf
Scientific Misconduct Check	21154-Scientific misconduct check.pdf
Scientific Editor Work List	21154-Scientific editor work list.pdf