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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109053-03
Application #
7486788
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Blair, Donald G
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$202,687
Indirect Cost
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Pozo, Karine; Hillmann, Antje; Augustyn, Alexander et al. (2015) Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis. Oncotarget 6:12080-93
Yu, Xiao-Min; Jaskula-Sztul, Renata; Ahmed, Kamal et al. (2013) Resveratrol induces differentiation markers expression in anaplastic thyroid carcinoma via activation of Notch1 signaling and suppresses cell growth. Mol Cancer Ther 12:1276-87
Yu, Xiao-Min; Phan, TramAnh; Patel, Priyesh N et al. (2013) Chrysin activates Notch1 signaling and suppresses tumor growth of anaplastic thyroid carcinoma in vitro and in vivo. Cancer 119:774-81
Pozo, Karine; Castro-Rivera, Emely; Tan, Chunfeng et al. (2013) The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell 24:499-511
Xiao, Yuling; Jaskula-Sztul, Renata; Javadi, Alireza et al. (2012) Co-delivery of doxorubicin and siRNA using octreotide-conjugated gold nanorods for targeted neuroendocrine cancer therapy. Nanoscale 4:7185-93
Lubner, Sam J; Kunnimalaiyaan, Muthusamy; Holen, Kyle D et al. (2011) A preclinical and clinical study of lithium in low-grade neuroendocrine tumors. Oncologist 16:452-7
Phan, TramAnh; Yu, Xiao-Min; Kunnimalaiyaan, Muthusamy et al. (2011) Antiproliferative effect of chrysin on anaplastic thyroid cancer. J Surg Res 170:84-8
Pinchot, Scott N; Jaskula-Sztul, Renata; Ning, Li et al. (2011) Identification and validation of Notch pathway activating compounds through a novel high-throughput screening method. Cancer 117:1386-98
Mohammed, Tabraiz A; Holen, Kyle D; Jaskula-Sztul, Renata et al. (2011) A pilot phase II study of valproic acid for treatment of low-grade neuroendocrine carcinoma. Oncologist 16:835-43
Truong, Matthew; Cook, Mackenzie R; Pinchot, Scott N et al. (2011) Resveratrol induces Notch2-mediated apoptosis and suppression of neuroendocrine markers in medullary thyroid cancer. Ann Surg Oncol 18:1506-11

Showing the most recent 10 out of 42 publications