Caring for Carcinoid Foundation

The Caring for Carcinoid Foundation (CFCF) reports all research progress by our funded scientists. This policy is based on our commitment to transparency and accountability.

CFCF-funded scientists are making rapid progress in unlocking the genetic causes of carcinoid and developing novel, targeted therapies.

We invite you to review their exciting research progress.

Progress Reports
Peer-Reviewed Publications
ASCO Presentations

Nature Clinical Practice Oncology (February 2009)

An article entitled, "Treatment of advanced disease in patients with well-differentiated neuroendocrine tumors” appeared in the peer-reviewed journal, Nature Clinical Practice Oncology.

The authors are: Diane L Reidy*, Laura H Tang and Leonard B Saltz.

The authors state, "Advances in the understanding of tumor biology have led to the identification of important cellular processes involved in the pathogenesis of NETs, and
agents that target these processes have now entered clinical trials."

Read the Nature Clinical Practice Oncology article

Cancer Research (January 2009)

An article entitled, "O6-Methylguanine DNA Methyltransferase Deficiency and
Response to Temozolomide-Based Therapy in Patients with Neuroendocrine Tumors” appeared in the peer-reviewed journal, Cancer Research, published by the American Association for Cancer Research ( AACR).

The authors are: Matthew H. Kulke, Jason L. Hornick, Christine Frauenhoffer, Susanne Hooshmand, David P.Ryan, Peter C. Enzinger, Jeffrey A. Meyerhardt, Jeffrey W. Clark, Keith Stuart, Charles S. Fuchs, and Mark S. Redston.

The authors state, "MGMTdeficiency, measured by immunohistochemistry, is more common in pancreatic neuroendocrine tumors than in carcinoid tumors as is treatment response to temozolomide-based therapy. Absence of MGMT may explain the sensitivity of some pancreatic neuroendocrine tumors to treatment.”

Read the Clinical Cancer Research Article

Gastroenterology (November 2008)

"An article entitled "Gastrointestinal Neuroendocrine Tumors: Pancreatic Neuroendocrine Tumors" appeared in the peer-reviewed journal, Gastroenterology, the official journal of the American Gastroenterological Association (AGA) Institute.

The authors are David Metz and Robert Jensen.

The authors state:

"Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators because of their unusual and florid symptoms as well as the insights they provide into the actions of gastrointestinal (GI) hormones."

Read the Gastroenterology Article

Cancer Research (November 2008)

"An article entitled "A Prospective Study of Meat and Fat Intake in Relation to Small Intestinal Cancer" appeared in the peer-reviewed journal, Cancer Research, published by the American Association for Cancer Research ( AACR).

The authors are Amanda J. Cross, Michael F. Leitzmann, Amy F. Subar, Frances E. Thompson, Albert R. Hollenbeck, and Arthur Schatzkin.

The authors state:

"In our study, there was a clear positive association between saturated fat intake and carcinoid tumors of the small intestine..."

Read Cancer Research Article

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Journal of National Cancer Institute (September 2008)

"An article enttitled "Priorities for Improving the Management of Gastroenteropancreatic Neuroendocrine Tumors" was publsihed in the peer-reviewed, Journal of the National Cancer Institute. THis article describes the National Cancer Institute summit meeting on gastroenteropancreatic neuroendocrine and carcinoid tumors that was held in September 2007 to present the currently accepted standards of care for patients with these tumors and to identify areas requiring investigation and development. The Caring for Carcinoid Foundation was active in organizing and funding this meeting.

The authors are Irvin M. Modlin, Steven F. Moss, Daniel C. Chung, Robert T. Jensen, and Elizabeth Snyderwine

The authors summarize the results of the summit meeting as follows:

"The most pressing needs were public and physician education, identification of molecular markers for early diagnosis and therapeutic monitoring, improved imaging modalities and molecular prognostication, development of a standardized pathological classification system, and creation of regional centers of expertise with tumor and laboratory data banks. In addition, adequately validated neuroendocrine tumor models and cell lines should be established to investigate the molecular mechanism involved in the control of their growth and secretion, and to facilitate the development of specific therapies that should be examined in well-designed multicenter studies of defined patient groups."

Read the Journal of the National Cancer Institute Article

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Gastroenterology (September 2008)

An article entitled "Hoxc6 Is Overexpressed in Gastrointestinal Carcinoids and Interacts With JunD to Regulate Tumor Growth" appeared in the peer-reviewed journal, Gastroenterology. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

The authors are Kotoyo Fujiki, Eva-Maria Duerr, Hirotoshi Kikuchi, Aylwyn NG, Ramnik J. Xavier, Yusuke Mizukami, Takaaki Imamura, Matthew H. Kulke, and Daniel C. Chung.

The authors state:

"A novel molecular pathway has been identified that links Hoxc6 with oncogenic signaling through the activator protein-1 pathway in carcinoid tumorigenesis."

The authors also state:

"Potential strategies include inhibition of Hoxc6 directly, inhibition of the interaction between Hoxc6 and JunD, or inhibition of the AP-1 signaling pathway in general. Regardless, these observations have revealed a pathway that underlies the molecular pathogenesis of carcinoid tumors."

Read Gastroenterology Article

Journal of Clinical Oncology (July 2008)

An article entitled "Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors" appeared in the peer-reviewed journal, Journal of Clinical Oncology. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

The authors are Matthew H. Kulke, Heinz-Josef Lenz, Neal J. Meropol, James Posey, David P. Ryan, Joel Picus, Emily Bergsland, Keith Stuart, Lesley Tye, Xin Huang, Jim Z. Li, Charles M. Baum, and Charles S. Fuchs.

The authors state:

"In conclusion, treatment with sunitinib resulted in objective tumor responses in patients with pancreatic neuroendocrine tumors. Whether sunitinib may also be associated with an antitumor effect in carcinoid tumors could not be clearly determined in this nonrandomized study. Further investigation of sunitinib in the randomized setting or in combination with other agents is warranted in these diseases. "

Read Journal of Clinical Oncology article

Genes, Chromosomes and Cancer (July 2008)

An article entitled "High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss" appeared in the peer-reviewed journal, Genes, Chromosomes, and Cancer. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

The authors are Matthew H. Kulke, Ellen Freed, Derek Y. Chiang, Juliet Philips, David Zahrieh, Jonathan N. Glickman, and Ramesh A. Shivdasani.

The authors state:

"In summary, focal deletions and high-level amplifications, as reported in other malignancies, appear to be rare in small bowel carcinoid tumors; regional amplifications that occur in the region of the antiapoptotic gene DAD1 and the G protein-coupled odorant receptor gene OR4A5 on chromosome arm 11p warrant further investigation. Instead, ileal carcinoid tumors carry large regions of genetic loss or modest gain in both primary and metastatic lesions, suggesting that such changes occur relatively early in carcinoid pathogenesis and that modest gains in CN may have a strong impact on cell behavior in this disease. "

Read Genes, Chromosomes and Cancer article

Molecular and Cellular Biology (May 2008)

An article entitled "Requirement of the Tissue-Restricted Homeodomain Transcription Factor Nkx6.3 in Differentiation of Gastrin-Producing G Cells in the Stomach Antrum" appeared in the peer-reviewed journal, Endocrine-Related Cancer. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

The authors are Michael Y. Choi, Anthony I. Romer, Yang Wang, Melissa P. Wu, Susumu Ito, Andrew B. Leiter, and Ramesh A. Shivdasani.

The authors state:

"These data suggest that Nkx6.3 acts independently of Ngn3; both transcription factors are necessary, but neither alone is sufficient to enable gastrin gene expression and G-cell differentiation. The difference between the narrow Nkx6.3/ phenotype and the diverse endocrine effects of loss of other transcription factors (Fig. 6A) suggests that the latter operate early in endocrine cell ontogeny or independently in multiple lineages. In contrast, our results reveal Nkx6.3 as a selective regulator that localizes in mature cells at the bases of antral gland units and appears to influence G- versus D-cell identity in a cell-autonomous fashion."

Read Molecular and Cellular Biology article

Endocrine-Related Cancer (March 2008)

An article entitled "Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis" appeared in the peer-reviewed journal, Endocrine-Related Cancer. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

The authors are Eva-Maria Duerr, Yusuke Mizukami, Aylwin Ng, Ramnik J Xavier, Hirotoshi Kikuchi, Vikram Deshpande, Andrew L Warshaw, Jonathan Glickman, Matthew H Kulke, and Daniel C Chung.

The authors state:

"In summary, we have identified a novel set of genes that may play a role in the pathogenesis and progression of PNETs and GI-NETs. Our results reveal a correlation with the WHO histologic classification on a molecular level... By improving the molecular classification of these tumor subtypes, we may ultimately enhance our ability to predict tumor behavior, provide important new insights into the molecular biology and tumor pathogenesis, and design the next generation of targeted therapies."

Read Endocrine-Related Cancer article

Developmental Biology (November 2007)

An article entitled "The retinoblastoma protein, RB, is required for gastrointestinal endocrine cells to exit the cell cycle, but not for hormone expression" appeared in the peer-reviewed journal, Developmental Biology. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

The authors are Yang Wang, Subir K. Ray, Philip W. Hinds, and Andrew B. Leiter.

The authors state:

"In summary, our work suggests that RB is important for enteroendocrine cells to undergo cell cycle arrest as they differentiate. However, enteroendocrine cells differentiate to express their characteristic hormones in the absence of functional RB or p107 proteins without exiting the cell cycle. The importance of RB for inducing cell cycle arrest of developing enteroendocrine cells is quite variable between different endocrine lineages and different gastrointestinal organs."

Read Developmental Biology article

Clinical Cancer Research (August 2007)

An article entitled, "The Development and Characterization of a Human Midgut Carcinoid Cell Line" appeared in the peer-reviewed journal, Clinical Cancer Research. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

The authors are George Van Buren II, Asif Rashid, Anthony D. Yang, Eddie K. Abdalla, Michael J. Gray, Wenbiao Liu, Ray Somcio, Fan Fan, E. Ramsay Camp, James C. Yao, and Lee M. Ellis.

The authors state:

"Gastrointestinal neuroendocrine tumors (NET) are rare heterogeneous tumors that hypersecrete neuropeptides. The scarcity of good gastrointestinal NET models has limited the ability to study potential therapeutic agents. We describe and characterize the establishment of a human midgut carcinoid tumor cell line carcinoid tumor 2 (CNDT2). ...

The establishment of this human midgut carcinoid tumor cell line may serve as a useful model system for studying cell biology and novel targeted agents in preclinical models."

Read Clinical Cancer Research article

Proceedings of the National Academy of Sciences (July 2007)

An article entitled, "Enteroendocrine precursors differentiate independently of Wnt and form serotonin expressing adenomas in response to active B-catenin" appeared in the peer-reviewed journal, Proceedings of the National Academy of Sciences. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

The authors are Yang Wang, Maryann Giel-Moloney, Guido Rindi, and Andrew B. Leiter.

The authors state:

"These results provide direct evidence that some intestinal lineages are specified independently of the Wnt pathway and may lead to a better understanding of the spectrum of neuroendocrine differentiation frequently seen in human gastrointestinal cancer."

Read Proceedings of the National Academy of Sciences article

Journal of Clinical Oncology (August 2006)

An article entitled, "Phase II Study of Recombinant Human Endostatin in Patients With Advanced Neuroendocrine Tumors" appeared in the peer-reviewed journal, Journal of Clinical Oncology. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

The authors are Matthew H. Kulke, Emily K. Bergsland, David P. Ryan, Peter C. Enzinger, Thomas J. Lynch, Andrew X. Zhu, Jeffrey A. Meyerhardt, John V. Heymach, William E. Fogler, Carolyn Sidor, Ann Michelini, Kate Kinsella, Alan P. Venook, and Charles S. Fuchs.

The authors conclude:

"Endostatin is a 20-kd proteolytic fragment of collagen XVIII that, in preclinical studies, has been shown to have antiangiogenic and antitumor activity. Both preclinical and human phase I studies of recombinant human endostatin (rhEndostatin) suggested activity in neuroendocrine tumors, which are known to be hypervascular. We therefore performed a multicenter phase II study of rhEndostatin in patients with carcinoid or pancreatic neuroendocrine tumors.

... rhEndostatin was associated with minimal toxicity. However, among 40 patients assessable for radiologic response, none experienced partial response to therapy, as defined by WHO criteria. The median steady-state trough level achieved after dose escalation was 331 ng/mL, within the postulated therapeutic range.

Treatment with rhEndostatin did not result in significant tumor regression in patients with advanced neuroendocrine tumors."

Read Journal of Clinical Oncology article

Digestive Diseases and Sciences (2006)

An article entitled, "Alkaline Phosphatase Predicts Survival in Patients with Metastatic Neuroendocrine Tumors" appeared in the peer-reviewed journal, Digestive Diseases and Sciences. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

The authors are Thomas E. Clancy, MD, Tanya P. Sengupta, Jessica Paulus, Fawzia Ahmed, Mei-Sheng Duh, and Matthew Kulke, MD.

The authors conclude:

"The clinical course of patients with metastatic neuroendocrine tumors is highly variable. While some patients experience an indolent clinical course over many years, other patients may rapidly succumb to their disease. Little is known about prognostic factors in these patients, making decisions regarding their management more difficult.

We performed a retrospective analysis of 137 patients with metastatic neuroendocrine tumors referred to our institution for treatment. Potential prognostic factors were evaluated using multivariate survival analysis. The median overall survival of patients in our cohort was 6.0 years, although the range of survival times was broad (48 days to 23.4 years). Alkaline phosphatase levels above normal were predictive of shorter survival in both univariate and multivariate analysis. Elevated chromogranin A levels were also associated with shorter survival in univariate analysis; in a multivariate analysis, however, this correlation was no longer significant. There was no association between survival and gender, primary tumor site, or presence or absence of carcinoid syndrome. Elevated alkaline phosphatase is a robust adverse prognostic factor for survival in patients with metastatic neuroendocrine tumors and may be superior to chromogranin A in this setting. Close monitoring of alkaline phosphatase levels may be useful when considering initiation or changes of therapy in patients with metastatic neuroendocrine tumors."

Read Digestive Diseases and Sciences article

Journal of Clinical Oncology (January 2006)

Dr. Matthew Kulke published clinical trial results in the January 20, 2006 issue of the peer-reviewed journal, Journal of Clinical Oncology. This article recognizes the Caring for Carcinoid Foundation for its research funding support.

Dr. Kulke conducted a Phase II trial to treat neuroendocrine patients with a combination of temozolomide and thalidomide. This drug combination shrank neuroendocrine tumors in 25 percent of the study participants and was biochemically active against tumors in 40 percent of the participants.

In announcing his results, Dr. Kulke said:

"Neuroendocrine tumors are among the most vascular, or blood vessel-filled, tumors that exist, so it made sense to test chemotherapy in combination with an angiogenesis inhibitor like thalidomide, which blocks blood vessel growth. ... In many patients, the therapy produced a significant response, usually with less severe side effects than with older, standard chemotherapy regimens."

In his article, Dr. Kulke states:

"In conclusion, we report that the combination of temozolomide and thalidomide seems to be an active oral regimen for the treatment of metastatic neuroendocrine tumors and represents a reasonable treatment alternative to older, intravenous regimens for this patient population. Our study suggests that this regimen may be more active in pancreatic endocrine tumors than in carcinoid tumors. Further studies to more precisely assess the relative efficacy of this regimen in pancreatic endocrine and carcinoid tumors are warranted, as are studies to assess the relative contributions of temozolomide and thalidomide to the antitumor activity observed with this combination."

Read press release

Read Journal of Clinical Oncology article

ASCO Presentations

ASCO 2009 Gastrointestinal Cancers Symposium

At the 2009 ASCO Annual Meeting, researchers delivered several presentations about carcinoid and neuroendocrine tumor research. Abstracts include:

Rudolf Arnold, MD, FRCP - “Placebo-controlled, double-blind, prospective, randomized study of the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID study group.”

Summary: Octreotide LAR was given to patients with metastatic neuroendocrine midgut tumors. The investigators found that patients treated with octreotide LAR had a 67% risk reduction of tumor progression compared with patients receiving placebo.
View Dr. Arnold abstract

Mace L Rothenberg, MD –“AMG 479 monotherapy to treat patients with advanced GI carcinoid tumors: A subset analysis from the first-in-human study.”

Summary: AMG 479 was used, for the first time, to treat patients with advanced gastrointestinal carcinoid tumors. The phase I study to evaluate toxicities, adverse events, and tumor response showed AMG479 to be well tolerated and have promising anti-tumor activity. A phase 2 study in patients with GI carcinoid tumors is planned.
View Dr. Rothenberg abstract

Edward M Wolin, MD – “Pasireotide LAR in patients with metastatic carcinoid tumors: Pharmacokinetics (PK) and safety results from a randomized, multicenter, phase I study.”

Summary: In a phase I study of pasireotide long-acting-release (LAR) formulation, patients with metastatic carcinoid tumors received intramuscular pasireotide monthly. The safety and tolerability assessment showed pasireotide LAR was well tolerated, and adverse events were consistent with those seen with the pasireotide subcutaneous formulation. The availability of a long-acting release formulation of pasireotide will provide patients and clinicians with a convenient treatment option. A multinational Phase III study of pasireotide LAR is enrolling patients with metastatic carcinoid tumors.
View Dr. Wolin abstract

James C Yao, MD – “A phase II trial of daily oral RAD001 (everolimus) in patients with metastatic pancreatic neuroendocrine tumors (NETs) after failure of cytotoxic chemotherapy.”

Summary: RAD001 was given to patients with metastatic pancreatic neuroendocrine tumors (NETs). The investigators found that daily oral dosing of RAD001 demonstrates antitumor activity and is well tolerated among patients with low-intermediate grade pancreatic NET who previously failed on systematic chemotherapy regimens.
View Dr. Yao abstract

Jonathan R Strosberg, MD – “Phase II study of sunitinib malate following hepatic artery embolization for metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs).”

Summary: Patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with liver metastases received sunitinib, following a series of selective arterial embolizations. Among the 14 patients studied, the results showed that sunitinib could be safely administered following hepatic artery embolization. Longer follow-up is needed to assess whether this strategy results in prolonged time to tumor progression.
View Dr. Strosberg abstract

2007 ASCO Annual Meeting

At the 2007 ASCO Annual Meeting, researchers delivered several presentations about carcinoid and neuroendocrine tumor research. These presentations included:

James Yao, MD - "Phase II study of RAD001 (everolimus) and depot octreotide (sandostatin LAR) in advanced low grade neuroendocrine carcinoma (LGNET)"
Timothy Hobday, MD - "MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study"
Matthew Kulke, MD - "Prediction of response to temozolomide (TMZ)-based therapy by loss of MGMT expression in patients with advanced neuroendocrine tumors (NET)"

View ASCO presentations

2006 ASCO Annual Meeting

At the 2006 ASCO Annual Meeting, researchers delivered several presentations about carcinoid and neuroendocrine tumor research. These presentations included:

Matthew Kulke, MD - "A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors"
Timothy Hobday, MD - "A phase II trial of gefitinib in patients with progressive metastatic neuroendocrine tumors: A Phase II Consortium study"
James Yao, MD - "Phase II study of RAD001 (everolimus) and depot octreotide (Sandostatin LAR) in patients with advanced low grade neuroendocrine carcinoma"
Carlo Bello, MS - "Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors: VEGF, IL-8, and soluble VEGF receptors 2 and 3"

View Dr. Kulke abstract

View Dr. Kulke presentation poster

View Dr. Hobday abstract

View Dr. Yao abstract

View Bello abstract

2005 ASCO Annual Meeting

Dr. Matthew Kulke recently completed a Phase II study of SU11248 with carcinoid and islet cell patients. SU11248 is a new, targeted drug similar to Gleevec that is being developed by Pfizer. SU11248 targets multiple tyrosine kinase growth signals and acts as an angiogenesis inhibitor.

Dr. Kulke presented his clinical trial results to the 2005 American Society of Clinical Oncology Annual Meeting. Dr. Kulke concluded:

"SU11248 is well tolerated and is associated with modest response rates and a high level of stable disease when used as a single agent in patients with advanced unresectable neuroendocrine tumors. Additional studies to explore the clinical benefit of SU11248 in patients with neuroendocrine tumors are warranted."

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View presentation (video and slides)