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Caring for Carcinoid Foundation

Peer-Reviewed Publications

Menin Epigenetically Represses Hedgehog Signaling in MEN1 Tumor Syndrome

Publication: Cancer Research

Publication Date: 05/2013

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Multiple endocrine neoplasia type 1 (MEN1) is an inherited tumor syndrome that includes susceptibility to pancreatic islet tumors. This syndrome results from mutations in the MEN1 gene, encoding menin. Although menin acts as an oncogenic cofactor for mixed lineage leukemia (MLL) fusion protein–mediated histone H3 lysine 4 methylation, the precise basis for how menin suppresses gene expression and proliferation of pancreatic beta cells remains poorly understood. Here, we show that menin ablation enhances Hedgehog signaling, a proproliferative and oncogenic pathway, in murine pancreatic islets. Menin directly interacts with protein arginine methyltransferase 5 (PRMT5), a negative regulator of gene transcription. Menin recruits PRMT5 to the promoter of the Gas1 gene, a crucial factor for binding of Sonic Hedgehog (Shh) ligand to its receptor PTCH1 and subsequent activation of the Hedgehog signaling pathway, increases repressive histone arginine symmetric dimethylation (H4R3m2s), and suppresses Gas1 expression. Notably, MEN1 disease-related menin mutants have reduced binding to PRMT5, and fail to impart the repressive H4R3m2s mark at the Gas1 promoter, resulting in its elevated expression. Pharmacologic inhibition of Hedgehog signaling significantly reduces proliferation of insulinoma cells, and expression of Hedgehog signaling targets including Ptch1, in MEN1 tumors of mice. These findings uncover a novel link between menin and Hedgehog signaling whereby menin/PRMT5 epigenetically suppresses Hedgehog signaling, revealing it as a target for treating MEN1 tumors

Authors: Buddha Gurung,Zijie Feng,Daniel V. Iwamoto, Austin Thiel1, Guanghui Jin,Chen-Min Fan, Jessica M.Y. Ng, Tom Curran, Xianxin Hua

Free Abstract

Clinical presentation, recurrence, and survival in patients with neuroendocrine tumors: results from a prospective institutional database

Publication: Endocrine Related Cancer

Publication Date: 01/2013

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The rarity of neuroendocrine tumors (NET) has contributed to a paucity of large epidemiologic studies of patients with this condition. We characterized presenting symptoms and clinical outcomes in a prospective database of over 900 patients with NET. We used data from patient questionnaires and the medical record to characterize presenting symptoms, disease-free survival (DFS) and overall survival (OS). The majority of patients in this database had gastroenteropancreatic NET. The median duration of patient-reported symptoms prior to diagnosis was 3.4 months; 19.5% reported durations from 1 to 5 years, 2.5% from 5 to 10 years and 2% greater than 10 years. The median DFS among patients with resected small bowel NET or pancreatic NET was 5.8 yrs and 4.1 years, respectively. After correcting for left truncation bias, the median OS was 7.9 yrs for advanced small bowel NET and 3.9 yrs for advanced pancreatic NET. Chromogranin A (CGA) above twice the upper limit of normal was associated with shorter survival times (HR 2.8 (1.9, 4.0) p<0.001) patients with metastatic disease, regardless of tumor subtype. Our data suggest that while most NET patients are diagnosed soon after symptom onset, prolonged symptom duration prior to diagnosis is a prominent feature of this disease. Though limited to observations from a large referral center, our observations confirm the prognostic value of CGA, and suggest that median survival durations may be shorter than reported in other institutional databases.

Authors: Ter-Minassian M, Chan JA, Hooshmand SM, Brais LK, Daskalova A, Heafield R, Buchanan L, Qian ZR, Fuchs CS, Lin X, Christiani DC, Kulke MH.

Free abstract

Pancreatic Neuroendocrine and Carcinoid Tumors: What's New, What's Old, and What's Different?

Publication: Current Oncology Reports

Publication Date: 03/2012

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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.

Free abstract

The same pocket in menin binds both MLL and JUND but has opposite effects on transcription

Publication: Nature

Publication Date: 02/2012

Nature Cover

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.

Free abstract

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 Lancet

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.

Free abstract

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

Journal of Nuclear Medicine

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.

Free abstract

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

PNAS

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

Free abstract

Altered Telomeres in Tumors with ATRX and DAXX Mutations

Publication: Science

Publication Date: 06/2011

science

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

Read the abstract in Science

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

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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

Read the abstract in the JCO

Interventional Radiology Y-90 Liver Cancer-busting Treatment: Safe, Fast, Extends Life

Publication: Society of Interventional Radiology News

Publication Date: 03/2011

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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.

Read the abstract from SIR news

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