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June 15 Clinical Cancer Research Highlights

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Selected Articles from the June 15, 2008 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Clinical Cancer Research is published. Click on the article title to view the complete article.

View the Table of Contents for the June 15 issue of Clinical Cancer Research.

CCR Focus:
Focus on Phase 0 Clinical Trials

Doroshow et al.

Page 3657

CCR Focus June 15 Phase 0 clinical trials are nontherapeutic studies that are used to assess whether a drug has had an impact on its intended target. Although phase 0 trials are expected to reduce the time needed for new drug development, a number of issues have been raised regarding these trials. In this CCR Focus, guest editor Dr. James Doroshow examines Phase 0 trial design. Several issues surrounding Phase 0 trials are discussed, including the need to streamline the approval process for Phase 0 trials, the need to willingly abandon drugs that do not modulate their target in a Phase 0 trial, and the need to develop assays sooner in the drug development process so that they can be used with confidence in Phase 0 trials.
 

CIP2A Involvement in Gastric Cancer

Li et al.

Page 3722

Li et al. CIP2A is an oncogenic factor that stabilizes c-MYC protein and drives cellular transformation. Li and colleagues determined whether CIP2A expression can serve as a marker for gastric cancer and investigated the mechanism underlying CIP2A-mediated transformation and cell proliferation. They found that 32 of 37 gastric cancer samples (87%) overexpressed CIP2A, whereas the majority of normal gastric mucosa lacked CIP2A expression. Further, reducing CIP2A levels in tumor cell lines substantially inhibited growth and induced senescence. These results suggest CIP2A may be a useful diagnostic marker and therapeutic target in gastric cancer. 

A Mouse Model of Hemangioma Generation

Sausville et al.

Page 3948

Sausville et al. Neoplasms are thought to harbor elusive cancer stem cells that are difficult to kill and can perpetuate the disease. Using a novel animal model that allows in vivo delivery of oncogenes to hemangioblasts, Sausville and colleagues recapitulated the generation of hemangioma stem cells. They found that targeting PyMT, a known oncogene, to hemangioblasts using recombinant retroviral vectors resulted in fatal hemorrhagic disease in mice. The hem­angiomatous lesions resembled those seen in Kasabach-Merritt syndrome and other human hemangiomas, which are also believed to originate from transformed endo­thelial progenitors. The ability to target endothelial progenitors in vivo may facilitate phenotypic and func­tional characterization of hemangioma stem cells and the development of antiangiogenic therapy. 

Page 3984

Willmore et al.Increased activity of the DNA double-strand break repair enzyme, DNA-dependent protein kinase (DNA-PK), is known to correlate with resistance to chemotherapy in chronic lymphocytic leukemia (CLL). Willmore and colleagues used a specific DNA-PK inhibitor, NU7441, to determine whether targeting DNA-PK would sensitize CLL cells to chemotherapy. Ex vivo assays on 54 characterized CLL cases (including some with p53 dysfunction and some with increased DNA-PK activity) showed that NU7441 could sensitize cells to fludarabine and chlorambucil by increasing the amount of drug-induced DNA damage. Further, they found that high DNA-PK protein expression predicted for shorter time-to-treatment. These data validate targeting DNA-PK in poor prognosis CLL and implicate increased DNA-PK activity in CLL disease progression. 

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