Pancreatic cancer (PC) is one of the leading causes of cancer death in the United States with a median survival shorter than six months. Pancreatic cancer is very deadly, because it is resistant to conventional treatments and it rapidly disseminates to the lymphatic system and remote organs. Hence, it is important to identify novel drugs that target the underlying molecular events of PC growth and interfere with PC development by blocking cell division and selectively inducing tumor cell apoptosis. One particular gene that has gained attention in recent years due to its importance in a number of cancers is Forkhead Box M1 (FoxM1). FoxM1 is a transcription factor that regulates the expression of a number of genes that are involved in cell cycle regulation and metastasis. In our preliminary studies, we identified the antibiotic thiazole compounds Siomycin A and thiostrepton as potent inhibitors of FoxM1. The goal of this proposal is to investigate the role of FoxM1 in the development of pancreatic cancer and to determine the molecular mechanisms of action of Siomycin A/thiostrepton against FoxM1 and pancreatic cancer. In the first specific aim we will determine how Siomycin A/thiostrepton inhibit the transcriptional activity and expression of FoxM1 and we will test the hypothesis that downregulation of FoxM1 is the key event that leads to Siomycin A/thiostrepton-induced apoptosis in PC cells. To evaluate the efficacy of FoxM1 inhibitors as anticancer agents in vivo, we will use them against xenograft tumors developed in athymic mice by human pancreatic cancer cell lines, which are sensitive to thiazole antibiotics in vitro. The effect of Siomycin A/thiostrepton treatment on FoxM1 expression and growth of xenograft tumors will be examined in these mice. These data may not only help to develop new drugs against pancreatic cancer, but they will also facilitate better understanding of the role of FoxM1 in the etiology of PC. If the thiazole antibiotics have low toxicity and lead to pancreatic tumor regression in mice, we will conclude that these compounds may have a potential for further clinical development against pancreatic cancer.

Public Health Relevance

Pancreatic cancer is one of the leading causes of cancer death in the United States with a median survival shorter than six months. Pancreatic cancer is very deadly, because it is resistant to conventional treatments and it rapidly disseminates to the lymphatic system and remote organs. Therefore, it is important to identify novel targets for cancer therapy that will help to interfere with development of pancreatic cancer by blocking cell division and selectively inducing tumor cell apoptosis. One particular gene that has gained attention in recent years due to its overexpression in a number of cancers is Forkhead Box M1 (FoxM1). FoxM1 is a transcription factor that regulates the expression of a number of genes that are involved in cell proliferation and metastasis. In our preliminary studies, we identified the antibiotic thiazole compounds Siomycin A and thiostrepton as potent inhibitors of FoxM1. The goal of this proposal is to investigate the role of FoxM1 in the development of pancreatic cancer and to determine if Siomycin A/thiostrepton will be able to inhibit growth of pancreatic tumors in vitro and vivo. These data may not only help to develop new drugs against pancreatic cancer, but they will also facilitate better understanding of the role of FoxM1 in the etiology of pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA134615-02
Application #
7638585
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2008-06-16
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2009
Total Cost
$247,275
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Gartel, Andrei L (2017) FOXM1 in Cancer: Interactions and Vulnerabilities. Cancer Res 77:3135-3139
Gartel, Andrei L (2012) Mechanisms of apoptosis induced by anticancer compounds in melanoma cells. Curr Top Med Chem 12:50-2
Halasi, Marianna; Gartel, Andrei L (2012) Suppression of FOXM1 sensitizes human cancer cells to cell death induced by DNA-damage. PLoS One 7:e31761
Wang, Ming; Halasi, Marianna; Kabirov, Kasim et al. (2012) Combination treatment with bortezomib and thiostrepton is effective against tumor formation in mouse models of DEN/PB-induced liver carcinogenesis. Cell Cycle 11:3370-2
Wang, Ming; Gartel, Andrei L (2012) Combination with bortezomib enhances the antitumor effects of nanoparticle-encapsulated thiostrepton. Cancer Biol Ther 13:184-9
Pandit, Bulbul; Gartel, Andrei L (2011) Proteasome inhibitors suppress expression of NPM and ARF proteins. Cell Cycle 10:3827-9
Bhat, Uppoor G; Jagadeeswaran, Ramasamy; Halasi, Marianna et al. (2011) Nucleophosmin interacts with FOXM1 and modulates the level and localization of FOXM1 in human cancer cells. J Biol Chem 286:41425-33
Wang, Ming; Gartel, Andrei L (2011) Micelle-encapsulated thiostrepton as an effective nanomedicine for inhibiting tumor growth and for suppressing FOXM1 in human xenografts. Mol Cancer Ther 10:2287-97
Pandit, Bulbul; Bhat, Uppoor G; Gartel, Andrei L (2011) Proteasome inhibitory activity of thiazole antibiotics. Cancer Biol Ther 11:43-7
Wang, Ming; Gartel, Andrei L (2011) The suppression of FOXM1 and its targets in breast cancer xenograft tumors by siRNA. Oncotarget 2:1218-26

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