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Research Breakthroughs for Neuroendocrine and Carcinoid Tumors

  • Investigators in Dana-Farber Brigham Cancer Center's Neuroendocrine and Carcinoid Tumors Program are international leaders in conducting innovative research and providing precise and patient-focused care. Under the direction of Matthew Kulke, MD, the program's multidisciplinary team of experts continually leverage the latest genomic technologies to learn more about the fundamental biology behind this complex set of diseases, and lead breakthrough clinical trials to improve treatment options for patients.

    Our program helped to advance two targeted therapies — sunitinib and everolimus — that were approved by the Food and Drug Administration in 2011 and changed the standard of care for pancreatic neuroendocrine tumors.

    Kulke and his team are building on this pioneering progress by continuing to launch basic scientific studies to identify the molecular mechanisms responsible for neuroendocrine tumor growth. This work is driving the discovery of novel targets and is expediting the development of new and more impactful treatment strategies — expanding the options available for patients.

    Leadership in expanding treatments for carcinoid tumors

    Everolimus: repurposing an existing neuroendocrine drug

    Dana-Farber investigators are leading an array of studies to uncover new treatments for patients with carcinoid tumors. These rare malignancies continue to present treatment challenges due to the historical lack of understanding about their origin and growth. Matthew Kulke, MD, and his team make up one of the leading programs in the world for treating and studying carcinoid tumors, and they are dedicated to developing more impactful therapies to improve patient outcomes.

    For instance, Kulke and his collaborators recently examined the safety and efficacy of the drug everolimus against advanced carcinoid tumors. The study results revealed that everolimus is effective when used to target this set of tumors, and led its approval by the Food and Drug Administration in 2016 as a treatment for carcinoid tumors.

    Telotristat: targeting the effects of carcinoid syndrome

    Kulke led an international study to evaluate the drug telotristat in treating carcinoid syndrome, a set of severe symptoms that can occur in patients with carcinoid tumors. After publishing findings in July 2014 in Endocrine-Related Cancer revealing that this drug was safe and impactful, Kulke helped to lead a pivotal, international clinical trial to test this drug in patients with carcinoid syndrome who had not responded to standard treatments, and found that telotristat helped relieve some of the most challenging symptoms.

    Advancing new treatment strategies

    Multiple approaches to inhibit angiogenesis

    Scientists now understand that angiogenesis — the formation of new blood vessels — plays a particularly important role in driving neuroendocrine tumor growth due to these tumors' highly vascular nature, which makes them especially reliant on building new blood vessels. Kulke led initial studies of the angiogenesis inhibitor sunitinib in pancreatic neuroendocrine tumors, which led to its approval as a standard treatment for these tumors in 2011.

    Jennifer Chan MD, MPH, clinical director of the Neuroendocrine and Carcinoid Tumors Program, and her colleagues are exploring several strategies to inhibit this key process in neuroendocrine tumors. Chan is currently leading a clinical trial to determine if the drug aflibercept, which is approved to treat colorectal tumors, is effective against neuroendocrine tumors. Aflibercept inhibits angiogenesis by binding to certain proteins called vascular endothelial growth factors (VEGFs) that play a key role in this process. Chan aims to learn whether aflibercept can target VEGFs in neuroendocrine tumors to help prevent these tumors from developing the blood vessels necessary to grow and spread.

    Chan has also developed a study to evaluate another promising angiogenesis inhibitor called ramucirumab. This work builds on the findings of Charles Fuchs, MD, MPH, who recently led an international clinical trial in nearly 30 countries that propelled the FDA to approve ramucirumab as the first-ever targeted agent for gastric cancer. Expanding on this discovery, Kulke and Chan are exploring whether this drug can help to treat patients with neuroendocrine tumors. Repurposing existing compounds can expedite the drug development process, so this study could quickly reveal a new treatment option.

    In a separate study, Kulke worked with collaborators to evaluate the drug pazopanib, another VEGF inhibitor. In the June 2015 Lancet Oncology, the team published their discovery that treatment with pazopanib elicited a positive response in patients with neuroendocrine tumors. These findings recently led to a larger-scale national study of the drug to further test its efficacy against neuroendocrine tumors.

    Strategic use of therapies in combination

    In addition to uncovering novel drugs, investigators aim to understand how best to strategically apply each new therapy and whether these agents are more effective when used alone or combined with other compounds. Kulke led a multi-institution cooperative clinical trial to test everolimus in combination with another angiogenesis inhibitor called bevacizumab. He discovered that this combination was effective in patients with advanced or metastatic pancreatic neuroendocrine tumors, and that together, the two drugs helped to improve progression-free survival and response rates. Kulke presented these findings at the 2015 American Society of Clinical Oncology annual meeting.

    View our current neuroendocrine and carcinoid clinical trials.

    Clinical and laboratory research

    Researchers in the Neuroendocrine Tumor Program have been working to unlock the molecular mechanisms underlying the growth and development of neuroendocrine tumors. Dana-Farber Cancer Institute's neuroendocrine tumor database is at the core of this effort. One of the first and largest databases of its kind, it now includes information and tumor samples from more than 1,000 patients.

    Understanding tumor-environment interactions

    While it is critical to understand which alterations are driving tumors, it is also important for investigators to consider the surrounding tumor environment. Understanding how tumors interact with the rest of the body can reveal unique ways to expand treatment options and maximize therapeutic impact.

    Laboratory models: Expediting drug development

    Working with Matthew Kulke, Michaela Bowden, PhD, and Ewa Sicinska, MD, of Dana-Farber's Center for Molecular Oncologic Pathology, are using the carcinoid model developed at Dana-Farber — one of the few such models in existence — to learn more about the drivers of carcinoid tumors. Through an ongoing genome-wide association study in collaboration with investigators at the Harvard School of Public Health, the team has already uncovered new potential targets and alterations that may be linked to tumor growth. They are continuing to advance their laboratory model so that they can further evaluate these targets and test new drugs — a critical step in uncovering new, more impactful treatments for patients with carcinoid tumors.

    The team's studies using this model also revealed that the carcinoid tumor microenvironment — the cellular environment around a tumor — appears to play a significant role in driving carcinoid tumor development and growth. This finding changed the way that Dana-Farber investigators study this disease, expanding their focus from mutations within cancer cells to the surrounding tissue. Kulke, Bowden, and Sicinska are working to identify the precise mechanisms behind how tumors use their environment to spread, with the ultimate aim of uncovering ways to block this activity and thereby halt tumor growth.

    Immunotherapy: Evaluating possibilities

    Kulke and his team are studying the role of the immune environment in neuroendocrine tumors. Using Dana-Farber's biobank — one of the first and largest databases of neuroendocrine tumor samples — the investigators are exploring the expression of key immune proteins in neuroendocrine tumors and in the surrounding microenvironment, as well as assessing any potential associations with clinical outcomes. Through this study, the team aims to better understand how neuroendocrine tumors interact with the immune system, and whether these tumors are likely to respond to existing or future immunotherapies. This work demonstrates the importance of studying the area surrounding a tumor and how that tumor interacts with the rest of the body and its many complex functions.

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