Neuroendocrine Tumors: Progress at Last

Matthew Kulke, MD
Dana-Farber Cancer Institute
Boston, MA 02115

Neuroendocrine tumors present a paradox: while they are generally indolent in nature, they have historically been difficult to treat. While the inherent nature of these tumors may not be changing, the therapeutic options available to treat neuroendocrine malignancies are evolving more rapidly than at any time in the recorded past. In particular, “targeted” therapies hold promise for patients suffering from advanced disease. Advances in our basic understanding of neuroendocrine tumor biology, many of which have been supported by the Caring for Carcinoid Foundation, promise to yield additional information that will be useful in the development of novel treatments.

In some respects, the unique clinical characteristics of neuroendocrine tumors may also be their Achilles heel. Neuroendocrine tumors have long been known to be highly vascular, and more recent studies have demonstrated elevated expression levels of vascular endothelial growth factor (VEGF), together with its receptor (VEGFR). The development of specific therapies targeting the VEGF pathway created an opportunity to advance beyond traditional cytotoxic therapies in this disease. Bevacizumab, a monocolonal antibody directing against VEGF was one of the first such treatments evaluated in neuroendocrine tumors. A clinical trial performed by investigators at MD Anderson Cancer Center suggested that treatment with bevacizumab was associated with objective tumor responses and improvement in progression-free survival when compared to treatment with alpha interferon.1 A simultaneous study, led by investigators at Dana-Farber Cancer Institute, demonstrated that treatment with sunitinib, a tyrosine kinase inhibitor targeting not only the VEGF receptor but also PDGFR, RET, and c-Kit, resulted in tumor responses in 16% of pancreatic neuroendocrine tumor patients.2 Most recently, similar antitumor activity was reported with the tyrosine kinase inhibitor sorafenib, in a study performed by investigators from the Mayo Clinic.3

VEGF pathway inhibitors are not the only promising new treatment approach for neuroendocrine tumors. The mammalian target of rapamycin (mTOR) functions downstream of a number of receptor tyrosine kinases, including the VEGF receptor, and serves a central role in regulating cell growth. Inhibitors of mTOR represent a second class of “targeted” agents that have shown preliminary evidence of activity in neuroendocrine tumors. While the results of a phase II study evaluating temsirolimus were disappointing, responses were observed in 18% of carcinoid patients and 20% of pancreatic neuroendocrine tumor patients in a phase II study of the oral mTOR inhibitor everolimus. 4,5

These initial results have now led to the development of large, multi-institutional randomized studies to more definitively evaluate the efficacy of VEGF pathway inhibitors and mTOR inhibitors in neuroendocrine tumors. One such study, led by the Southwest Oncology Group (S0518), is comparing treatment with bevacizumab alone to treatment with alpha interferon in patients with advanced carcinoid tumors. In a parallel effort, an international industry-sponsored study is comparing treatment with sunitininib to placebo in pancreatic neuroendocrine tumor patients. Everolimus is currently being evaluated in two definitive phase III studies, one enrolling pancreatic neuroendocrine tumors and the other carcinoid tumors.

Evidence that both VEGF pathway inhibitors and mTOR inhibitors are active in neuroendocrine tumors suggests that other agents targeting the broadly-defined receptor tyrosine kinase/PI3-Kinase/AKT/mTOR cell signaling pathway may also be active in this disease type. Newer agents in development, including inhibitors of IGF1-R and PI3-Kinase, target different aspects of this same pathway. Preliminary evidence of activity in neuroendocrine tumors has already been reported with an IGF1-R inhibitor; it will be interesting to observe if activity with IGF1-R inhibitors and related compounds is confirmed.6

Amid the excitement associated with these novel agents, it is easy to forget that older treatment strategies may still be effective. Given the high prevalence of somatostatin receptor expression on neuroendocrine tumors, as well as the efficacy of “cold” somatostatin in controlling symptoms, the use of radiolabelled somatostatin analogs is inherently appealing. A number of different radiopeptides incorporating Indium-111, Yttrium-90, or Lutecium-177 have been associated with both biochemical and radiologic responses in early studies. Rigorous studies of these agents are anticipated in the near future, to better define their efficacy and long-term toxicity.

The use of cytotoxic chemotherapy may also still play a role in the treatment of selected patients with neuroendocrine tumors. Streptozocin-based regimens are active in patients with pancreatic neuroendocrine tumors; in fact, streptozocin is currently the only FDA-approved drug for this indication.7 Newer chemotherapy regimens incorporating temozolomide may provide a more easily tolerated alternative to streptozocin-based therapy, and are currently being evaluated in clinical studies.8,9 In one such study, supported by the Caring for Carcinoid Foundation, expression of the DNA repair enzyme MGMT appeared to predict response to temozolomide-based therapy in pancreatic neuroendocrine tumor patients.10 These findings, if confirmed, could help predict which patients will benefit from temozolomide-based treatment regimens.

Important advances have also been made in our understanding of neuroendocrine tumor biology. As recently as 3 years ago, we knew little about the genetic features of carcinoid tumors, nor were cell lines or animal models available to study this disease. In large part due to the efforts of the Caring for Carcinoid Foundation, these challenges are being overcome. Investigators from Tufts-New England Medical Center have shown that manipulation of the Wnt developmental signaling pathway leads to serotonin-secreting tumors in mice, providing a potentially important clue regarding the developmental pathways important in carcinoid tumor growth.11 A team from MD Anderson Cancer Center created a new human small intestine carcinoid cell line, providing, for the first time, a tool for studying growth pathways and new drugs in this tumor subtype.12 Investigators from the University of Wisconsin have already examined one of these growth pathways—the Raf/MEK/ERK pathway—and found that inhibiting this pathway may be helpful in stopping carcinoid tumor growth.13 Using a database of human tumor samples and clinical information, investigators from Massachusetts General Hospital and Dana-Farber Cancer Institute have recently reported gene expression analyses and genomic alterations in neuroendocrine tumors, providing early genetic maps of this disease.14,15

The ongoing clinical and scientific investigations of neuroendocrine tumors represent an important and exciting step toward the discovery of new treatments for neuroendocrine tumor patients. We can realistically look forward to a time in the near future when neuroendocrine tumors will be not only indolent but also susceptible to a broad range of therapeutic agents.


References

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