Neuroendocrine Tumors: Novel Approaches in the Age of Targeted Therapy

ABSTRACT: The diagnosed incidence rate of neuroendocrine tumors (NETs) is on the rise. Prevalence calculations show NETs to be more common then previously thought. Although generally thought to be indolent, advanced NETs remain incurable and are resistant to most cytotoxic agents. The available biologic agents have limited activity against these tumors. Novel and active agents are clearly needed. The recent emergence of molecularly targeted therapy in oncology has brought renewed interest in the development of novel agents for this group of diseases. This paper will review the molecular biology of NETs, promising novel targeted therapy approaches including agents targeting angiogenesis and mammalian target of rapamycin (mTOR) pathways, as well as pivotal phase III studies that may set new standards of care for this disease.

One hundred years after Oberndorfer coined the word “carcinoid,” neuroendocrine tumors (NETs) are thought to be rare tumors characterized by the capacity for hormone production and often an indolent course. Recent data from population-based registries have shown a significant rise in the diagnosed incidence of NETs over the past 3 decades. The possible explanation for this increasing incidence is multifactorial, including better diagnostics, improved awareness, and other undetermined environmental and genetic factors. Our analysis of the Surveillance, Epidemiology, and End Results (SEER) program database showed an age-adjusted incidence of 5.25 cases per 100,000 in 2004, accounting for just over 1% of diagnosed malignancies.[1] This, together with a generally longer associated survival, leads to a prevalence of 35 per 100,000, which exceeds that of esophageal, gastric, pancreatic, or hepatobiliary cancer.[1]

The management of NETs is generally guided by histology. High-grade or poorly differentiated NETs have an aggressive course, and their management parallels that of small-cell carcinoma of the lung.

In this manuscript, we will focus on the well- to moderately differentiated groups of neuroendocrine tumors that are more indolent but more resistant to cytotoxic chemotherapy. Today, “carcinoid” is typically used to describe a well- to moderately differentiated NET arising outside the pancreas. Those arising from the pancreas-pancreatic NET (PNET), or islet cell carcinoma-are recognized to have a different genetic profile,[2] more aggressive clinical course,[1] and different pattern of response to cytotoxic chemotherapy.[3] These more differentiated tumors are also more likely to produce hormonal syndromes such as carcinoid syndrome (manifesting as flushing and diarrhea) and Verner-Morrison syndrome (watery diarrhea, hypokalemia, and achlorhydria, or WDHA syndrome). Advanced NETs are incurable. The median overall survival duration among patients with advanced well- to moderately differentiated NETs of the small bowel, cecum, appendix, pancreas, and rectum are 65, 55, 31, 27, and 26 months, respectively.[1]

Current Systemic Therapy Options

Therapeutic objectives for patients with NETs include control of the paraneoplastic hormonal syndrome and tumor growth. Treatment often includes the use of somatostatin analogs (SSAs), interferon, chemotherapy, liver-directed therapy, surgical resection, or ablation of hepatic metastases, and radiation therapy for palliative benefit. Peptide receptor radiotherapy with [177Lu-DOTA0,Tyr3] octreotate or [90Y-DOTA0,Tyr3] octreotide represents an additional option in Europe.

Somatostatin Analogs

Somatostatin receptors (SSTRs) are expressed on the majority of NETs. Somatostatin is a peptide hormone that decreases hormone leading to inactivation of the gene encoding menin located on chromosome 11 (11q13). The classic syndrome includes neoplasia of the parathyroid glands, anterior pituitary, endocrine pancreas, and endocrine duodenum, but rarely adrenal neoplasms and neuroendocrine tumors of the lung, thymus, and stomach.[16] The MEN1 gene may also be involved in the tumorigenesis of sporadic carcinoid tumors. The loss of heterozygosity (LOH) on chromosome 11, the site of the MEN1 gene, is frequently found in pulmonary carcinoids.[16] Menin appears to be involved in the regulation of gene transcription through its interaction as part of a histone methyltransferase complex.[17] Menin also appears to be involved in the control of cell-cycle regulation through control of p27 expression.[18]

Neurofibromatosis (NF) and tuberous sclerosis (TSC) can manifest with benign lesions, such as hamartomas and astrocytomas, as well as together with well-differentiated tumors in the brain, heart, skin, kidney, lung, and endocrine pancreas.[19] The genes associated with TSC are TSC-1 (located on 9q34) and TSC-2 (located on 16p13.3), and they encode the proteins hamartin and tuberin, respectively. The development of PNETs in patients with TSC is thought to be particularly related to mutations in TSC2.[16] TSC-1/2 complex functions as our endogenous inhibitor of mTOR, and is normally expressed in neuroendocrine cells.[20] The loss of TSC function leads to constitutive activation of the mTOR pathway.

Patients with NF-1 may also develop ampullary of Vater carcinoids, as well as duodenal and pancreatic NETs.[16] The NF-1 gene is a tumor-suppressor gene that is located on 17q11.2 and encodes a protein called neurofibromin. The latter is also linked with mTOR through regulation of TSC function. It has been shown that NF-1 acts as a negative regulator of mTOR-specifically, LOH of the NF-1 gene results in the loss of neurofibromin expression, constitutive mTOR activation, and, therefore, tumor development.[21]

The main clinical features of VHL syndrome include retinal or central nervous system hemangioblastomas, clear cell renal carcinomas, pheocromocytomas, and pancreatic cystic tumors or PNETs. Pancreatic lesions can be seen in 20% to 75% of patients with VHL.[22] In the largest series with 94 VHL families, it was reported that the majority of pancreatic lesions were true cysts (91%), whereas NETs represented 12% of cases.[23] The VHL gene is a tumor-suppressor gene that is located on chromosome 3p25–26 and regulates hypoxia-induced cell proliferation and angiogenesis. Specifically, the VHL protein, acting mainly as E3 ubiquitin ligase, would target many proteins for degradation.

The most well known target of VHL protein is the hypoxia inducible factor 1α (HIF-1α).[16] Under hypoxic conditions, HIF-1α is produced, translocates to the nucleus, and combines with HIF-1β, initiating the transcription of hypoxia-regulated genes such as vascular endothelial growth factor (VEGF). PNETs, are generally vascular but continue to express a large amount of HIF-1α, suggesting that aberrant regulation of HIF-1α expression may be involved in pathogenesis. Allelic deletion at chromosome 3p, the site of the VHL gene, has also been described as occurring frequently in sporadic NETs.[24]

Molecular Genetics of Sporadic NETs

Outside of defined genetic syndromes, the genes responsible for the development of NETs are unknown. Recent studies using comparative genomic hybridization (CGH), or high-density single-nucleotide polymorphism arrays, suggest that the genetics of most sporadic NETs are far more complex than previously thought, and likely involve many genes in a multistep process in their development and progression. For example, on a genetic level, allelic deletion of chromosome 18 is frequently observed in midgut carcinoid tumors.[25] On an epigenetic level, hypomethylation of LINE-1 elements is associated with chromosome 18 loss.[26] The molecular genetics of PNETs is even more complex. Our most recent study, using a high-density single-nucleotide polymorphism array, showed a pattern of gain and loss across multiple chromosomes.[16]

Molecular Targeted Therapy

In recent decades, it has been established that the regulation and modulation of growth pathways are disturbed or mutated in tumor cells, which in turn lead to disruption of signaling pathways, accelerated cell proliferation, and growth. Promising novel targeted therapies in NETs in recent and ongoing clinical trials include (1) inhibitors of the VEGF pathway, such as the monoclonal antibody bevacizumab and small-molecule multikinase inhibitors sunitinib (Sutent) and sorafenib (Nexavar), and (2) inhibitors of mTOR, such as everolimus (RAD001, see Tables 1 and 2).

Receptor Tyrosine Kinase and VEGF Inhibitors

TABLE 1

Targeted Therapy in Neuroendocrine Tumors: Phase II Clinical Trials

Angiogenesis is a well-recognized requirement for tumor growth beyond a small size and is crucial to the process of metastasis. Low-grade NETs are known to be particularly vascular. VEGF, a potent promoter of angiogenesis, is expressed in both gastrointestinal and pulmonary carcinoid tumors.[27,28] Furthermore, recent studies have demonstrated the expression of both tyrosine kinase VEGF receptors[29] as well as non–tyrosine kinase VEGF receptors (neuropilin 2)[30] on carcinoid tumor cells.

Bevacizumab is a recombinant humanized monoclonal antibody that binds to and neutralizes the biologic activity of human VEGF-A. In a randomized phase II study conducted at M.D. Anderson, we observed a rapid and sustained decrease in tumor perfusion following treatment with octreotide and bevacizumab, as measured using functional computed tomography.[9] Clinical activity was evidenced by a response rate of 18% and an improved PFS rate at week 18 (95% vs 68%; P=.02; Table 1).[9] A larger confirmatory study (Table 2) sponsored by the Southwest Oncology Group (SWOG) and the National Cancer Institute (NCI), and supported by the Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, and North Central Cancer Treatment Group through the NCI’s Cancer Trials Support Unit, will compare the octreotide long-acting release (LAR) formulation and bevacizumab to octreotide LAR and interferon among patients with advanced carcinoid tumors (SWOG 0518, National Clinical Trial [NCT]00569127).

TABLE 2

Ongoing Random Assignment Phase III Study With Targeted Agents in Neuroendocrine Tumors

Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases (RTKs). These include platelet-derived growth factor receptors (PDGF-R) and VEGF receptors (VEGF-R), which play a role in both tumor angiogenesis and tumor cell proliferation. The simultaneous inhibition of these targets, therefore, leads to both reduced tumor vascularization and ultimately tumor shrinkage. In addition, sunitinib inhibits other RTKs such as RET, colony-stimulating factor receptor (CSF-1R), and FMS-like tyrosine kinase-3 (flt3). The originality of sorafenib lies in its simultaneous targeting of the Raf/Mek/Erk pathway. In this pathway, ras signaling often involves activation of Raf-1, a cytosolic serine/threonine kinase. Activated Raf-1 then phosphorylates mitogen-activated protein (MAP)/ERK kinase 1 and 2 (MEK1/2), which then activates downstream extracellular signal–regulated kinase 1 and 2 (ERK1/2).

In NETs, mutations causing elevated Raf-1 signaling are rarely detected in pathologic specimens.[31] Thus, the activity of sorafenib in NETs may not be related to its effect on Raf-1. Both sorafenib and sunitinib have been studied in the phase II setting (Table 1). In the recently reported study with sunitinib, the response rates among carcinoid and PNET patients were 2% and 17%, respectively. Median times to progression were 10 months for the carcinoid group and 8 months for the PNET group.[32] Similarly, the confirmed response rates for sorafenib among patients with carcinoid and PNET were 7% and 11%, respectively.[33] Median PFS durations were 8 and 12 months, respectively.

Studies with sunitinib and sorafenib have reported higher rates of adverse events. Approximately 89% of patients treated with sunitinib reported fatigue (24% grade 3).[32] Adverse events or withdrawal of consent (64%) were the most common reasons for discontinuation of sorafenib.[33] The activity of sunitinib among patient with PNETs will be confirmed in a multinational phase III study (Table 2).

mTOR Inhibitors

mTOR is a conserved serine/threonine kinase that regulates cell growth and metabolism in response to environmental factors and signaling downstream of receptor tyrosine kinases, such as insulin-like growth factor (IGF) receptor, VEGF receptor (VEGFR), and epidermal growth factor receptor (EGFR). While there are no known mutations in mTOR, the association of hereditary cancer syndromes involving the mTOR pathway with development of NETs suggests that mTOR may be an important target in NETs. Both temsirolimus (Torisel) and everolimus have been studied in NETs (Tables 1 and 2). In the temsirolimus study, 37 patients with progressive NETs received temsirolimus intravenously at 25 mg/wk.[34] The investigators found that temsirolimus had modest clinical activity, with a response rate of 5.6% and median time to progression of 6 months.

We recently reported our experience with octreotide LAR and everolimus in 60 patients with NETs. The intent-to-treat response rate was 20%. Per protocol response rates among patients with carcinoid and PNET were 17% and 27%.[35] Median PFS durations were 50 and 63 weeks, respectively. The role of everolimus in NETs was further confirmed in a multinational phase II study among patients with RECIST-documented progressive disease following cytotoxic chemotherapy (RAD001 In Advanced Neuroendocrine Tumors, or RADIANT-1).[36] A recent interim analysis showed a response rate of 8%, clinical benefit rate (partial response plus stable disease rates) of 77%, and median PFS of 9 months among patient receiving everolimus by central radiology review. Similarly, among patients receiving everolimus and octreotide, the response rate was 4%, clinical benefit rate was 82%, and median PFS was 13 months.[36]

Based on these encouraging results, two subsequent RADIANT studies are ongoing. RADIANT-2 is a randomized double-blind, placebo-controlled, multicenter phase III study of octreotide LAR with everolimus or placebo in patients with advanced carcinoid tumors. The RADIANT-2 study has completed accrual; results are expected in 2009. RADIANT-3 is a randomized double-blind, placebo-controlled, multicenter phase III study of everolimus or best supportive care in patients with advanced islet cell carcinoma.

Other Targeted Agents

Several other pathways have been studied in phase II studies in NETs with mixed success (Table 1). Since the introduction of imatinib mesylate (Gleevec), researchers have been interested in targeting the PDGF/c-kit/abl pathway in NETs. In a phase II clinical trial at M.D. Anderson, we treated 27 patients with advanced unresectable or metastatic carcinoid tumor using imatinib at 400 mg twice daily. We observed only a single response among the 27 patients treated.[37] Similarly, in a smaller study of 15 patients with various malignant endocrine tumors, no partial response was observed.[38]

EGFR plays an important role in the pathogenesis of many tumors. Investigators from Mayo Clinic reported overexpression of EGFR and activated EGFR in NETs. By immunohistochemical staining, EGFR positivity was seen in 100% of patients with carcinoids, and 22% of those with PNETs.[39] Gefitinib (Iressa) is an oral small-molecule tyrosine kinase inhibitor of EGFR. This set up the rationale for a study of oral gefitinib in patients with progressive metastatic NETs. A total of 96 patients received 250 mg of gefitinib daily. Although objective responses were rare, PFS rates at 6 months were 51% and 28% among patients with carcinoids and PNETs, respectively.[40]

The proteasome inhibitor bortezomib (Velcade) was also evaluated in NETs. In this phase II study, no responses were observed among 16 patients treated. Therefore, the study was terminated after interim analyses.[41]

Finally, with recent research implicating the role of menin in epigenetic regulation, the histone deacetylase (HDAC) inhibitor depsipeptide was studied in NETs.[42] Unfortunately, a high number of potentially serious cardiac events were noted among patients with NETs, and the study was terminated early. It is unclear if hormonal production and resultant carcinoid heart disease played a contributory role.

Given the limited activity of imatinib, gefitinib, bortezomib, and depsipeptide observed in these studies, it is unlikely that these agents will have a major role as monotherapy in NETs.

Summary

Although the introduction of somatostatin analogs has dramatically improved the management of hormonal syndromes caused by NETs, development of novel agents for the treatment of these tumors is clearly needed. Promising results from smaller phase II studies suggest that agents targeting angiogenesis and mTOR are active. Phase III studies examining the role of somatostatin analogs, bevacizumab, sunitinib, and everolimus in NETs are ongoing. Enrollment of eligible patients in these pivotal studies is encouraged.

Financial Disclosure:Dr. Phan serves on the speakers bureau and advisory board for Novartis.

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