Recent studies have shown that TGF-B inhibits cell proliferation by blocking cell cycle progression at the G1 phase of the cell cycle and hence, is thought to function as a tumor suppressor protein. Most human cancers appear to have lost their growth-inhibitory response to TGF-B. Our preliminary studies show that foregut cancers with inactivation of TGF-B signaling express high levels of cyclin D1 and CDK4 levels, suggesting that the deregulated expression of these proteins may contribute to the development of these tumors. Flavopiridol, an established Cdk inhibitor used in treatment protocols for certain cancers, is known to inhibit most known CDKs especially against CDKs 7, 8 and 9, is thought to be largely responsible for the toxic side effects caused by this drug in clinical trials. In light of these observations, we have screened a compound library of kinase inhibitors for CDK-4 specific inhibition and isolated two novel molecules (ON55290 and ON27900) which exhibit CDK4 inhibitory activity. In this application, we propose to carry out pre-clinical studies to test the usefulness of these molecules in gastrointestinal cancer therapy.
The aims of the proposal are: 1. To further validate the role of CDK4 in Elf+/-, Elf+/-:Smad3+/- tumor model system through evaluation of tumor incidence in CDK4+/V El+/- : CDK4+/-: Elf/Elf[+]-Smad4[+/-] and CDK4[+/-];Elf?/Elf+:Smad4+/- mice. 2. (a) To expand the chemical library in an effort to understand the structure-activity relationship (SAR) of CDK4 inhibitors and (b) to conduct a detailed kinetic analysis of CDK4 inhibition by ON55290 and ON27900 to gain critical information on the mechanisms by which these compounds elicit their inhibitory effects on CDK4. 3. To determine the molecular mechanisms by which ON55290 and ON27900 bring about growth arrest and death of human gastrointestinal cancer cells. 4. To assess the safety and pharmacokinetics of the candidate drug in animal models of gastrointestinal cancers that develop in the TGF-f3 inactivated state.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Zhi, Xiuling; Lin, Ling; Yang, Shaoxian et al. (2015) ?II-Spectrin (SPTBN1) suppresses progression of hepatocellular carcinoma and Wnt signaling by regulation of Wnt inhibitor kallistatin. Hepatology 61:598-612
Javle, Milind; Smyth, Elizabeth C; Chau, Ian (2014) Ramucirumab: successfully targeting angiogenesis in gastric cancer. Clin Cancer Res 20:5875-81
Kiriyama, Shigehisa; Yokoyama, Shozo; Ueno, Masaki et al. (2014) CEACAM1 long cytoplasmic domain isoform is associated with invasion and recurrence of hepatocellular carcinoma. Ann Surg Oncol 21 Suppl 4:S505-14
Xiao, Junfeng; Zhao, Yi; Varghese, Rency S et al. (2014) Evaluation of metabolite biomarkers for hepatocellular carcinoma through stratified analysis by gender, race, and alcoholic cirrhosis. Cancer Epidemiol Biomarkers Prev 23:64-72
Bailey, Ann M; Zhan, Le; Maru, Dipen et al. (2014) FXR silencing in human colon cancer by DNA methylation and KRAS signaling. Am J Physiol Gastrointest Liver Physiol 306:G48-58
Lim, Jeong A; Baek, Hye Jung; Jang, Moon Sun et al. (2014) Loss of *2-spectrin prevents cardiomyocyte differentiation and heart development. Cardiovasc Res 101:39-47
Mitra, Abhisek; Satelli, Arun; Yan, Jun et al. (2014) IL-30 (IL27p28) attenuates liver fibrosis through inducing NKG2D-rae1 interaction between NKT and activated hepatic stellate cells in mice. Hepatology 60:2027-39
Dibra, Denada; Mishra, Lopa; Li, Shulin (2014) Molecular mechanisms of oncogene-induced inflammation and inflammation-sustained oncogene activation in gastrointestinal tumors: an under-appreciated symbiotic relationship. Biochim Biophys Acta 1846:152-60
Huang, Chen; Du, Jiawei; Xie, Keping (2014) FOXM1 and its oncogenic signaling in pancreatic cancer pathogenesis. Biochim Biophys Acta 1845:104-16
Muñoz, Nina M; Katz, Lior H; Shina, Ji-Hyun et al. (2014) Generation of a mouse model of T-cell lymphoma based on chronic LPS challenge and TGF-? signaling disruption. Genes Cancer 5:348-52

Showing the most recent 10 out of 41 publications