A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas

Durán, Ignacio; Kortmansky, Jeremy; Singh, Deepak; Hirte, Hal W.; Kocha, Walter; Goss, Glenwood D.; Liu, Le; Oza, Amit M.; Nicklee, Trudey; J, Ho; Birle, Diana C.; Gr, Pond; Arboine, D; Dancey, Janet; Aviel‐Ronen, Sarit; Tsao, Ming‐Sound; Hedley, David W.; Ll, Siu

doi:10.1038/sj.bjc.6603419

Cited by 294 publications

(170 citation statements)

References 27 publications

Supporting

Mentioning

166

Contrasting

Unclassified

Order By: Relevance

“…Thus, our preclinical data would suggest that the more effective component in the everolimus and octreotide combination regimen may be the mTOR inhibitor. Notably, results from a multicenter phase II study of weekly temsirolimus in advanced progressive neuroendocrine tumors has recently been published (Duran et al 2006). Single agent temsirolimus demonstrated some clinical activity in this population: two patients (5.4%) achieved a confirmed partial response and a third patient had an unconfirmed partial response at the end of cycle 8 but discontinued therapy (not due to toxicity).…”

Section: Discussionmentioning

confidence: 99%

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

Moreno¹,

Akçakanat

Munsell³

et al. 2008

Endocrine Related Cancer

136

View full text Add to dashboard Cite

The mammalian target of rapamycin (mTOR) signaling pathway has emerged as a promising target for cancer therapy. Rapamycin inhibits mTOR activity but induces upstream signaling, leading to Akt activation, potentially limiting antitumor activity. Octreotide, a somatostatin analog, decreases phosphatidylinositol-3-kinase/Akt signaling in some models, and thus theoretically may enhance rapamycin's antitumor activity. The aim of this study was to determine the antitumor activity of rapamycin and octreotide as single agents and in combination in neuroendocrine tumors. In carcinoid cell lines BON-1 and NCI-H727, cell proliferation was significantly inhibited by rapamycin in vitro, although rapamycin treatment did lead to Akt phosphorylation. Octreotide had limited antiproliferative effects alone, and did not demonstrate synergistic or additive interactions with rapamycin. Furthermore, octreotide did not overcome rapamycin-induced Akt phosphorylation. In vivo, rapamycin alone caused significant tumor suppression. Octreotide alone did not inhibit in vivo tumor growth and did not enhance rapamycin-mediated growth inhibition. In conclusion, rapamycin causes significant growth inhibition in carcinoid tumor cell lines in vitro and in vivo, thus mTOR is a promising therapeutic target for neuroendocrine tumors. Octreotide does not enhance the efficacy of rapamycin's antiproliferative effects in the models tested, and does not inhibit rapamycin-mediated feedback activation of Akt. Further study is needed in order to determine whether octreotide or other somatostatin analogs enhance the efficacy of mTOR inhibitors in other models.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Moreno¹,

Akçakanat

Munsell³

et al. 2008

Endocrine Related Cancer

136

View full text Add to dashboard Cite

show abstract

“…However, determination of OBD for mTOR inhibitors is still elusive because there is currently no standard surrogate marker available for translating preclinical research results into clinical practice. In previous studies the phosphorylation status of mTOR targets such as S6 protein from surrogate tissue or tumour samples has been commonly used as a marker of mTOR kinase activity and the degree of mTOR inhibition (Boulay et al, 2004;Duran et al, 2006). Similarly, decreases of the proliferation marker Ki-67 in tumour samples have been correlated with mTOR inhibitor activity (Neshat et al, 2001;Tabernero et al, 2008).…”

mentioning

confidence: 99%

FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo

et al. 2009

View full text Add to dashboard Cite

This study aimed to test whether [ 18 F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg À1 per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses X5 mg kg À1 per day (tumour volume treated vs control (T/C): 51% for 5 mg kg À1 per day and 57% for 15 mg kg À1 per day). Correspondingly, doses X5 mg kg À1 per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg À1 per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg À1 per day and 52% for 15 mg kg À1 per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials.

show abstract

“…Weekly intravenous temsirolimus was associated with a response rate of 5.6% in a study of 37 patients with advanced progressive NET. Outcomes were similar between patients with carcinoid and PNET [41].…”

Section: Mtormentioning

confidence: 64%

Long-term Survival in Patient with Metastatic Pancreatic Neuroendocrine Tumor Treated by Variable Treatment

Kang¹,

Ryu²,

Lee³

et al. 2017

Korean J Pancreas Biliary Tract

View full text Add to dashboard Cite

Well-to-moderately differentiated neuroendocrine tumors of gastroesophageal and pancreatic origin (GEP-NETs) with liver metastasis are a heterogeneous group of malignancies for which a range of therapeutic options have been employed. Surgical resection of hepatic metastases or hepatic artery embolization may be beneficial in patients with hepatic-predominant metastatic disease. Patients with "carcinoid" syndrome and syndromes associated with functional pancreatic NET (PNET) can be effectively treated with somatostatin analogs. On the other hand, the efficacy of systemic chemotherapy for these patients is limited. A placebo-controlled, double-blind, prospective, and randomized study showed that octreotide LAR improves progression-free survival in patients with advanced midgut functional "carcinoids." In patients with advanced pancreatic NET, randomized, placebo-controlled studies have recently demonstrated that treatment with the tyrosine kinase inhibitor sunitinib or with mTOR inhibitor everolimus is associated with improved progression-free survival. Based on these studies, octreotide LAR, sunitinib, or everolimus are now considered as first-line therapeutic options in patients with advanced NET. Future studies will likely further define the role of these agents in patients with carcinoid liver metastasis and pancreatic NET liver metastasis.

show abstract

A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas

Cited by 294 publications

References 27 publications

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

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

FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo

Long-term Survival in Patient with Metastatic Pancreatic Neuroendocrine Tumor Treated by Variable Treatment

Contact Info

Product

Resources

About