Regulating Neuroendocrine Phenotype in Cancer

描述(申请人提供)：神经内分泌(NE)肿瘤，如类癌和胰岛细胞肿瘤，是孤立肝转移的第二大常见原因。由于这些NE病变的特征是激素分泌过多，这些肿瘤通常会引起衰弱的症状。除了手术，NE肿瘤患者可用的根治和姑息治疗方法有限，强调了开发其他形式治疗的必要性。我们最近发现，RAF-1在类癌和髓样甲状腺癌细胞中的过表达显著抑制了NE标志物的表达和5-羟色胺/降钙素的分泌，并抑制了对NE表型至关重要的转录因子hASH1的表达。在这项提案中，我们将确定hASH1在调节人NE细胞激素分泌方面的重要性。其次，我们将在初步的小鼠研究中表明，在NE肿瘤中RAF-1的激活可能会减少肿瘤的生长并抑制激素的产生。在第二个目标中，我们将建立两种复发/持续性NE肿瘤疾病的动物模型，以确定RAF-1激活是否会抑制体内肿瘤的生长和激素的产生。最后，我们将提供的数据表明，白介素6可能是RAF-1相关激素抑制的重要介质。我们将确定白介素6是否是RAF-1的唯一靶点。综上所述，这些研究应该确定RAF-1信号转导通路的调节是否在类癌患者的治疗中发挥潜在的作用。此外，这些发现可能使RAF-1通路的组成部分发展成为治疗NE肿瘤的治疗靶点。

DESCRIPTION (provided by applicant): Neuroendocrine (NE) tumors such as carcinoid and islet cell tumors are the second most common cause of isolated hepatic metastases. These tumors often cause debilitating symptoms due to the excessive hormonal secretion that characterizes these NE lesions. Besides surgery, there are limited curative and palliative treatments available to patients with NE tumors, emphasizing the need for development of other forms of therapy. We have recently shown that over-expression of raf-1 in human carcinoid and medullary thyroid cancer cells markedly suppresses NE marker expression and serotonin/calcitonin secretion, and silences expression of hASH1, a transcription factor critical to the NE phenotype. In this proposal, we will determine the importance of hASH1 in modulating hormone secretion by human NE cells. Secondly, we will show in preliminary murine studies that raf-1 activation in NE tumors may reduce tumor growth and suppress hormone production. In the second aim, we will develop 2 animal models of recurrent/persistent NE tumor disease to determine if raf-1 activation will inhibit tumor growth and suppress hormone production in vivo. Lastly, we will present data indicating that interleukin-6 may be an essential mediator of raf-1-associated hormone suppression. We will determine if interleukin- 6 is the sole target of raf-1. In summary, these studies should determine if modulation of the raf-1 signal transduction pathway could play a potential role in the management of patients with carcinoid tumors. Furthermore, these finding may permit development of components of raf-1 pathway as therapeutic targets in the treatment and palliation of NE tumors.