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Peer-Reviewed Publications
Pancreatic Neuroendocrine and Carcinoid Tumors: What's New, What's Old, and What's Different?
Publication: Current Oncology Reports
Publication Date: 03/2012
Well-differentiated neuroendocrine tumors (NETs) can be subdivided into carcinoid and pancreatic NETs (panNETs). Recently, two therapies have been FDA approved for progressive well-differentiated pancreatic NETs but have not been submitted for use in carcinoid tumors (Yao, Shah, Ito, et al., 2011; Raymond, Dahan, Raoul, et al., 2011). The first is sunitinib (Sutent®, Pfizer, Inc.), an orally administered, multitargeted receptor kinase inhibitor. The second targeted agent is everolimus (Afinitor®, Novartis Pharmaceuticals), a mammalian target of rapamycin (mTOR) inhibitor (Yao, Shah, Ito, et al., 2011). Both agents demonstrated improved progression-free survival but can also result in non-trivial toxicities and therefore, should only be considered in patients with progressing or symptomatic pancreatic NET. This review will discuss "new" NET therapies and provides an overview of liver directed and "older" cytotoxic treatment options. We also briefly outline "what's different" by describing a recent genetics report identifying genetic mutations in panNETs. Such a discovery could potentially be used to stratify treatment and such studies are currently being investigated.
Authors: Reidy-Lagunes, D., Thornton, R.
The same pocket in menin binds both MLL and JUND but has opposite effects on transcription
Publication: Nature
Publication Date: 02/2012
In a series of projects made possible in part by grant support from the Caring for Carcinoid Foundation, a group of researchers recently solved the three-dimensional crystal structure of menin. Menin is a protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene. Patients with MEN1 syndrome have a mutation in this gene. They have an increased risk of developing neuroendocrine tumors in several organs. Other CFCF-funded research projects show that sporadic pancreatic neuroendocrine tumors can have mutations in the MEN1 gene.
In an article published in the prestigious journal Nature, researchers reported two distinct cases in which menin may either promote or suppress gene expression, depending on the protein with which it interacts. Through structural and functional analysis, researchers provide a mechanistic explanation for how menin can both positively and negatively regulate gene transcription. These analyses are an important step in understanding how the menin protein may promote neuroendocrine tumor development.
Authors: Huang, J., Gurung, B., Wan, B., Matkar, S., Veniaminova, N., Wan, K., Merchant, J., Hua, X., Lei, M.
Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study
Publication: The Lancet
Publication Date: 11/2011
The RADIANT-2 trial was a Novartis-sponsored phase 3 study of everolimus plus octreotide LAR. 429 patients with low- or intermediate-grade, advanced, well-differentiated neuroendocrine tumors of varied origins with carcinoid syndrome from 16 countries participated in this randomized, double-blind study. The primary endpoint was progression-free survival.
The authors found that median progression-free survival was greater among patients who received everolimus and octreotide LAR rather than octreotide LAR and placebo.The most common side effects were mouth sores, rash, fatigue, and diarrhea.
The authors also note the need to confirm the efficacy of everolimus in future studies. Their analysis highlights some challenges in designing and interpreting clinical trials among neuroendocrine tumor patients. Please see full article for details or call CFCF at 617.948.2514 to discuss.
Authors: Pavel, M.E., Hainsworth, J.D., Baudin E., Peeters M., Hörsch, D., Winkler, R.E., Klimovsky, J., Lebwohl, D., Jehl, V., Wolin, E.M., Öberg, K., Van Cutsem, E., Yao, J.C.
Quality of Life in 265 Patients with Gastroenteropancreatic or Bronchial Neuroendocrine Tumors Treated with [177Lu-DOTA0,Tyr3]Octreotate
Publication: Journal of Nuclear Medicine
Publication Date: 09/2011
The researchers suggest that peptide receptor radiolabeled therapy (PRRT) can improve patients' self-reported quality of life. In particular, the authors noted improvements in patient-reported social and emotional well-being, insomnia, appetite loss, and diarrhea after treatment with Lutetium-177 (Lu-177).
The study tracked self-reported quality of life (QOL) among 265 Dutch patients diagnosed with gastroenteropancreatic and bronchial neuroendocrine tumors who were treated with Lu-177 at Erasmus Medical Center in the Netherlands.
Authors: Khan, S., Krenning, E., van Essen, M., Kam, B., Teunissen, J., and Kwekkeboom, D.
Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1
Publication: Proceedings of the National Academy of Sciences of the United States of America
Publication Date: 07/2011
Aberrations in epigenetic processes, such as histone methylation, can cause cancer. Retinoblastoma binding protein 2 (RBP2; also called JARID1A or KDM5A) can demethylate tri- and dimethylated lysine 4 in histone H3, which are epigenetic marks for transcriptionally active chromatin, whereas the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor promotes H3K4 methylation. Previous studies suggested that inhibition of RBP2 contributed to tumor suppression by the retinoblastoma protein (pRB). Here, we show that genetic ablation of Rbp2 decreases tumor formation and prolongs survival in Rb1+/− mice and Men1-defective mice. These studies link RBP2 histone demethylase activity to tumorigenesis and nominate RBP2 as a potential target for cancer therapy.
Authors: Wenchu Lin, Jian Cao, Jiayun Liu, Michael L. Beshiri, Yuko Fujiwara, Joshua Francis, Andrew D. Cherniack, Christoph Geisen, Lauren P. Blair, Mike R. Zou, Xiaohua Shen, Dan Kawamori, Zongzhi Liu, Chiara Grisanzio, Hideo Watanabe, Yoji Andrew Minamishima, Qing Zhang, Rohit N. Kulkarni, Sabina Signoretti, Scott J. Rodig, Roderick T. Bronson, Stuart H. Orkin, David P. Tuck, Elizaveta V. Benevolenskaya, Matthew Meyerson, William G. Kaelin, Jr. and Qin Yan
Altered Telomeres in Tumors with ATRX and DAXX Mutations
Publication: Science
Publication Date: 06/2011
CFCF funded researchers from Johns Hopkins found that mutations in two genes are linked to the formation of pancreatic neuroendocrine tumors, and that data suggests that the two genes are also linked to why the ends of cellular DNA (known as 'telomeres') lengthen in patients with cancer.
Authors: Christopher M. Heaphy, Roeland F. de Wilde, Yuchen Jiao, Alison P. Klein, Barish H. Edil, Chanjuan Shi, Chetan Bettegowda, Fausto J. Rodriguez, Charles G. Eberhart, Sachidanand Hebbar, Johan A. Offerhaus, Roger McLendon, B. Ahmed Rasheed, Yiping He, Hai Yan, Darell D. Bigner, Sueli Mieko Oba-Shinjo, Suely Kazue Nagahashi Marie, Gregory J. Riggins, Kenneth W. Kinzler, Bert Vogelstein, Ralph H. Hruban, Anirban Maitra, Nickolas Papadopoulos, Alan K. Meeker
Response, Survival, and Long-Term Toxicity After Therapy With the Radiolabeled Somatostatin Analogue [90Y-DOTA]-TOC in Metastasized Neuroendocrine Cancers
Publication: Journal of Clinical Oncology
Publication Date: 05/2011
In this study, neuroendocrine tumor patients were treated with repeated cycles of [90Y-DOTA]-TOC in order to document the long term outcome of the treatment. The authors state that the response to this treatment is associated with longer survival, and that somatostatin receptor imaging is predictive for both survival after [90Y-DOTA]-TOC treatment and occurrence of renal toxicity.
Authors: Anna Imhof, Philippe Brunner, Nicolas Marincek, Matthias Briel, Christian Schindler, Helmut Rasch, Helmut R. Mäcke, Christoph Rochlitz, Jan Müller-Brand and Martin A. Walter
Interventional Radiology Y-90 Liver Cancer-busting Treatment: Safe, Fast, Extends Life
Publication: Society of Interventional Radiology News
Publication Date: 03/2011
Based on a large multi-institutional study, new results show that higher doses of Y-90 are proven to be safe, provide results when chemotherapies have failed, preserved patients' quality of life, and can be done on an outpatient basis.
Authors: G. Siskin, Albany Medical Center, Albany, N.Y.; G. Wiseman, Mayo Clinic, Rochester, Minn.; W.S. Rilling, Medical College of Wisconsin, Milwaukee, Wis.; A. Benson III, M.F. Mulcahy, R. Salem, R.J. Lewandowski, K. Memon, Northwestern University, Chicago, Ill.; J.H. Geschwind, Johns Hopkins University, Baltimore, Md.
Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors
Publication: The New England Journal of Medicine
Publication Date: 02/2011
The authors state:
"Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors."
Authors: Eric Raymond, M.D., Ph.D., Laetitia Dahan, M.D., Ph.D., Jean-Luc Raoul, M.D., Ph.D., Yung-Jue Bang, M.D., Ivan Borbath, M.D., Ph.D., Catherine Lombard-Bohas, M.D., Juan Valle, M.D., Peter Metrakos, M.D., C.M., Denis Smith, M.D., Aaron Vinik, M.D., Ph.D., Jen-Shi Chen, M.D., Dieter Hörsch, M.D., Pascal Hammel, M.D., Ph.D., Bertram Wiedenmann, M.D., Ph.D., Eric Van Cutsem, M.D., Ph.D., Shem Patyna, Ph.D., Dongrui Ray Lu, M.Sc., Carolyn Blanckmeister, Ph.D., Richard Chao, M.D., and Philippe Ruszniewski, M.D.
Phase I Clinical Study of Seneca Valley Virus (SVV-001), a Replication-Competent Picornavirus, in Advanced Solid Tumors with Neuroendocrine Features
Publication: Clinical Cancer Research
Publication Date: 02/2011
“By studying the Seneca Valley Virus, we hope to define a novel, targeted therapeutic strategy for patients with neuroendocrine cancers, in particular more aggressive neuroendocrine cancers such as atypical carcinoid.” – Dr. Charles Rudin
Seneca Valley Virus (SVV-001) is a novel naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer. This article describes a first-in-human, first-in-class phase I clinical trial of this agent in patients with cancers with neuroendocrine features, including small cell lung cancer. Investigators concluded that intravenous SVV-001 administration in patients is well tolerated at doses up to 1011 vp/kg, with predictable viral clearance kinetics, intratumoral viral replication, and evidence of antitumor activity in patients with small cell lung cancer. Phase II clinical evaluation in small cell lung cancer is warranted, and has been initiated.
Authors: Charles M. Rudin, John T. Poirier, Neil N. Senzer, Joseph Stephenson Jr., David Loesch, Kevin D. Burroughs, P. Seshidhar Reddy, Christine L. Hann, and Paul L. Hallenbeck
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