PMID- 25092520
OWN - NLM
STAT- MEDLINE
DCOM- 20150522
LR  - 20231110
IS  - 1534-6277 (Electronic)
IS  - 1527-2729 (Print)
IS  - 1534-6277 (Linking)
VI  - 15
IP  - 3
DP  - 2014 Sep
TI  - Targeting the mTOR signaling pathway in neuroendocrine tumors.
PG  - 365-79
LID - 10.1007/s11864-014-0294-4 [doi]
AB  - Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies 
      characterized by variable but most often indolent biologic behavior. 
      Well-differentiated NETs can be broadly classified as either carcinoid or 
      pancreatic NET. Although they have similar characteristics on routine histologic 
      evaluation, the 2 tumor subtypes have different biology and respond differently 
      to treatment, with most therapeutic agents demonstrating higher response rates in 
      pancreatic NETs compared with carcinoid. Until recently, systemic treatment 
      options for patients with advanced NETs were limited. However, improvements in 
      our understanding of signaling pathways involved in the pathogenesis, growth, and 
      spread of NETs have translated into an expansion of treatment options. Aberrant 
      signaling through the mechanistic pathway of rapamycin (mTOR) pathway has been 
      implicated in neuroendocrine tumorigenesis. Additionally, altered expression of 
      mTOR pathway components has been observed in NETs and has been associated with 
      clinical outcomes. Targeting the mTOR pathway has emerged as an effective 
      treatment strategy in the management of advanced NETs. In a randomized, 
      placebo-controlled study of patients with advanced pancreatic NET, treatment with 
      the mTOR inhibitor everolimus was associated with improved progression-free 
      survival (PFS). Largely based upon these data, everolimus has been approved in 
      the United States and Europe for the treatment of patients with advanced 
      pancreatic NET. The activity of everolimus remains under investigation in 
      patients with carcinoid tumors. In a randomized study of patients with advanced 
      carcinoid tumors associated with carcinoid syndrome, the addition of everolimus 
      to octreotide was associated with improved PFS compared with octreotide. However, 
      the results did not meet the prespecified level of statistical significance based 
      on central review of radiographic imaging. Results from a randomized study 
      examining the efficacy of everolimus in patients with nonfunctional 
      gastrointestinal and lung NETs are awaited. In addition, further investigation is 
      needed to determine whether primary tumor site or other clinical and molecular 
      factors can impact response to mTOR inhibition. Although everolimus can slow 
      tumor progression, significant tumor reduction is rarely obtained. Targeting 
      multiple signaling pathways is a treatment strategy that may provide better tumor 
      control and overcome resistance mechanisms involved with targeting a single 
      pathway. Results of ongoing and future studies will provide important information 
      regarding the added benefit of combining mTOR inhibitors with other targeted 
      agents, such as VEGF pathway inhibitors, and cytotoxic chemotherapy in the 
      treatment of advanced NETs.
FAU - Chan, Jennifer
AU  - Chan J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline 
      Avenue, Boston, MA, 02215, USA, jang@partners.org.
FAU - Kulke, Matthew
AU  - Kulke M
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Curr Treat Options Oncol
JT  - Current treatment options in oncology
JID - 100900946
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Antineoplastic Agents/pharmacology/*therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
MH  - Humans
MH  - Molecular Targeted Therapy
MH  - Neuroendocrine Tumors/diagnosis/*drug therapy/etiology/*metabolism
MH  - Protein Kinase Inhibitors/pharmacology/*therapeutic use
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC4147239
EDAT- 2014/08/06 06:00
MHDA- 2015/05/23 06:00
PMCR- 2014/08/05
CRDT- 2014/08/06 06:00
PHST- 2014/08/06 06:00 [entrez]
PHST- 2014/08/06 06:00 [pubmed]
PHST- 2015/05/23 06:00 [medline]
PHST- 2014/08/05 00:00 [pmc-release]
AID - 294 [pii]
AID - 10.1007/s11864-014-0294-4 [doi]
PST - ppublish
SO  - Curr Treat Options Oncol. 2014 Sep;15(3):365-79. doi: 10.1007/s11864-014-0294-4.