[Show abstract][Hide abstract] ABSTRACT: Transforming growth factor beta (TGF-β) is an important regulator of cell growth, and loss of TGF-β signaling is a hallmark of carcinogenesis. The Smad3/4 adaptor protein β2-spectrin (β2SP) is emerging as a potent regulator of tumorigenesis through its ability to modulate the tumor suppressor function of TGF-β. However, to date the role of the TGF-β signaling pathway at specific stages of the development of hepatocellular carcinoma (HCC), particularly in relation to the activation of other oncogenic pathways, remains poorly delineated. Here we identify a mechanism by which β2SP, a crucial Smad3 adaptor, modulates cyclin dependent kinase 4 (CDK4), cell cycle progression, and suppression of HCC. Increased expression of β2SP inhibits phosphorylation of the retinoblastoma gene product (Rb) and markedly reduces CDK4 expression to a far greater extent than other CDKs and cyclins. Furthermore, suppression of CDK4 by β2SP efficiently restores Rb hypophosphorylation and cell cycle arrest in G(1) . We further demonstrate that β2SP interacts with CDK4 and Smad3 in a competitive and TGF-β-dependent manner. In addition, haploinsufficiency of cdk4 in β2sp(+/-) mice results in a dramatic decline in HCC formation compared to that observed in β2sp(+/-) mice. CONCLUSION: β2SP deficiency leads to CDK4 activation and contributes to dysregulation of the cell cycle, cellular proliferation, oncogene overexpression, and the formation of HCCs. Our data highlight CDK4 as an attractive target for the pharmacologic inhibition of HCC and demonstrate the importance of β2sp(+/-) mice as a model of preclinical efficacy in the treatment of HCC.
[Show abstract][Hide abstract] ABSTRACT: Treatment algorithms and survival for patients with metastatic colorectal cancer have changed dramatically over the past decade, largely due to the advent of molecularly targeted agents. The lessons we have learned with the integration of bevacizumab and cetuximab/panitumumab into standard therapy is that meaningful clinical end points can be achieved, and more patients with metastatic colorectal cancer are being cured or kept alive with a reasonable quality of life due to these new agents. As we enter this second decade of "modern therapy" for metastatic colorectal cancer, an ever-increasing number of new agents aimed at a variety of targets believed to promote cancer cell growth are being tested in clinical trials, and dozens of studies of novel targeted therapies are ongoing. Moreover, during the next decade, we can expect to see an explosion of new agents that will likely improve clinical outcomes further. This review focuses on molecularly targeted agents that are being used regularly in the treatment of colorectal cancer and highlights a number of new agents/targets that are being explored and appear promising in phase I or early phase II trials.
Gastrointestinal cancer research: GCR 01/2011; 4(1):15-21.
[Show abstract][Hide abstract] ABSTRACT: Small bowel cancers are rare, accounting for only about 6000 cases/year in the United States, approximately 25% of which are small bowel adenocarcinomas. Small bowel adenocarcinomas have traditionally been considered to be highly fatal due to their nonspecific presentation at the time of diagnosis, and to the lack of responsiveness to older chemotherapy regimens. However, that paradigm may be changing. Newer diagnostic techniques such as video capsule and double balloon enteroscopy may facilitate earlier diagnosis. In addition, modern chemotherapy regimens have produced improved response rates and survival rates, when compared to historical controls. Still, there remains great need for multi-institutional, cooperative group studies to define the optimal treatment of small bowel adenocarcinoma, both in the adjuvant and advanced/metastatic setting.
Current Treatment Options in Oncology 05/2009; 9(4-6):388-99. · 2.42 Impact Factor