February 1 2008 Clinical Cancer Research Highlights

Selected Articles from the February 1, 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 February 1 issue of Clinical Cancer Research.

A Chemokine Regulates Preferential Melanoma Metastasis

Amersi et al.

Page 638

Cutaneous melanoma is known to preferentially metastasize to the small intestine. As the chemokine receptor CCR9 and the chemoattractant CCL25 have both been implicated in the migration of lymphocytes to the small intestine, Amersi and colleagues hypothesized that the CCR9-CCL25 axis may be involved in cutaneous melanoma metastasis to the small intestine. They found that CCR9 is frequently expressed in metastatic melanoma samples taken from small intestine but not in samples taken from other sites. In additional in vitro experiments, Amersi and colleagues showed that the CCL25-dependent migration of melanoma cells could be inhibited by siRNA or antibodies against CCR9. These findings suggest that the CCR9-CCL25 axis facilitates cutaneous melanoma metastasis to the small intestine.

Heparanase as a Target in Prostate Cancer

Lerner et al.

Page 668

A detailed understanding of the mechanisms involved in metastasis and tumor growth in target organs during prostate cancer should lead to identification of new therapeutic targets and improved survival of patients. Heparanase is an enzyme that cleaves heparan sulfate, the main polysaccharide of the extracellular matrix. Using prostate carcinoma tissue microarrays analysis and a number of in vitro and in vivo models of prostate cancer, Lerner and colleagues demonstrated that heparanase directly contributes to prostate tumor growth in bone, as well as to the ability of prostate carcinoma to metastasize to distant organs. In vivo administration of siRNA resulted in marked regression of prostate tumor in a mouse host, validating the potential of heparanase as a target for prostate tumor treatment.

Clinical Efficacy of the HDAC Inhibitor Belinostat

Steele et al.

Page 804

Histone deacetylase (HDAC) inhibitors alter gene expression patterns and can promote cellular differentiation, cell cycle arrest, and apoptosis. In a phase 1 trial, Steele and colleagues show that the novel hydroxamate HDAC inhibitor Belinostat is well tolerated and displays promising clinical activity. Belinostat displays linear pharmacokinetics, but the AUC for histone acetylation (a biomarker of drug activity) shows a plateau at the maximum tolerated dose, suggesting achievement of the optimum biological effect. Patients with stable disease after treatment with Belinostat showed increased levels of apoptosis in epithelial tumors, based on biomarker analysis. Fatigue was a commonly observed side effect, but preliminary data suggest it may be mediated by increased levels of IL-6.

Diabody-Based Radioimmunotherapy for Breast Cancer

Robinson et al.

Page 875

Successful radioimmunotherapy strategies depend on matching the physical and biological properties of the radioisotope and antibody, respectively. In preclinical studies, Robinson and colleagues examined the effectiveness of pairing the anti-HER2 C6.5 diabody (an engineered antibody based molecule) with the potent alpha-emitting radioisotope 211At. Treatment of mice bearing HER2-positive established human breast tumor xenografts with a single dose of 211At-SAPS C6.5 diabody resulted in a significant, dose-dependent delay in tumor growth as compared with negative controls, with a complete response rate of 60% at the highest dose level. These experiments show that radioimmunotherapy with the 211At-SAPS C6.5 diabody holds promise as an effective treatment for HER2-positive solid tumors.

February 1 2008 Clinical Cancer Research Highlights

Selected Articles from the February 1, 2008 Issue

A Chemokine Regulates Preferential Melanoma Metastasis

Heparanase as a Target in Prostate Cancer

Clinical Efficacy of the HDAC Inhibitor Belinostat

Diabody-Based Radioimmunotherapy for Breast Cancer

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