Neuroendocrine tumors (NET) comprise several rare cancers, including pancreatic neuroendocrine tumors (approximately 4 cases per every 1,000,000 people)1 and carcinoid tumors (approximately 2 cases per every 100,000 people).2 Pancreatic neuroendocrine tumors are also known as islet cell tumors. Carcinoid tumors can originate in any part of the body, but most originate in the gastrointestinal (GI) tract.
Deregulation of several signaling pathway components upstream from mTOR have been associated with neuroendocrine tumors, including TSC1/TSC2,3,4 IGF-1/IGF-1R,5 and EGF/EGFR.5 In addition, many patients with neuroendocrine tumors have a defective von Hippel-Lindau (VHL) protein, which leads to HIF-1α accumulation and tumor angiogenesis.6
Currently, surgery is the only curative therapy for neuroendocrine tumors.
Unfortunately, the majority of patients with neuroendocrine tumors present with nonresectable or metastatic disease.7 The treatment of choice for patients with nonresectable pancreatic islet cell tumors is combination chemotherapy; however median survival for pancreatic islet cell patients treated with a combination regimen is estimated to be 2 to 3 years.8,9 In carcinoid, no chemotherapy regimen has demonstrated a response rate of greater than 15%.2
Clearly, additional therapies for neuroendocrine tumors are needed. Because of the involvement of TSC1/TSC2, IGF-1/IGF-1R, EGF/EGFR and VHL in neuroendocrine tumors, mTOR inhibitors are currently being investigated for the treatment of neuroendocrine tumors. Several clinical trials are planned or underway.
References:
- Barakat MT, Meeran K, Bloom SR. Neuroendocrine tumours. Endocrine-Related Cancer. 2004;11:1-18.
- Schnirer II, Yao JC, Ajani JA. Carcinoid—a comprehensive review. Acta Oncologica. 2003;42:672-692.
- Verhoef S, van Diemen-Steenvoorde R, Akkersdijk WL, et al. Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood. Eur J Pediatr. 1999;158:284-287.
- Francalanci P, Diomedi-Camassei F, Purificato C, et al. Malignant pancreatic endocrine tumor in a child with tuberous sclerosis. Am J Surg Path. 2003;27:1386-1389.
- Duran I, Salazar R, Casanovas O, et al. New drug development in digestive neuroendocrine tumors. Annals Oncol. 2007;18:1307-1313.
- Hammel PR, Vilgrain V, Terris B, et al. Pancreatic involvement in von Hippel-Lindau disease. Gastroenterology. 2000;119:1087-1095.
- Warner RRP. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. 2005;128:1668-1684.
- Kouvaraki MA, Ajani A, Hoff P, et al. Flourouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004;22:4762-4771.
- McCollum AD, Kulke MH, Ryan DP, et al. Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol. 2004;27:485-488.
