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April 2008 Molecular Cancer Therapeutics Highlights

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Selected Articles from the April 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 Molecular Cancer Therapeutics is published. Click on the article title to view the complete article.

View the Table of Contents for the April 2008 issue of Molecular Cancer Therapeutics

Spotlight on Clinical Response:
BRAF/NRAS Mutations Status Important in HSP90 Inhibitors

Banjeri et al.

Page 737

Oncogenic BRAF and NRAS mutations are frequent in malignant melanoma. BRAF that is activated by the common V600E and other mutations, as well as by upstream NRAS mutations, has been shown to require the molecular chaperone heat shock protein 90 (HSP90) for stabilization and is depleted by the HSP90 inhibitor 17-AAG. Banerji and colleagues explored the possible relationship between tumor BRAF and NRAS mutations and clinical response to 17-AAG in six patients with metastatic malignant melanoma who received pharmacologically active doses of 17-AAG as part of a phase I clinical trial. Their preliminary results suggest that BRAF and NRAS mutation status should be determined in prospective phase II studies of HSP90 inhibitors in melanoma. 

bcl-2 Silenced in Mantle Cell Lymphoma

Tucker et al.

Page 749

Bcl-2 silencing in Mantle cell lymphoma (MCL) can lead to alteration of several important cell signaling pathways. Tucker and colleagues investigated the cell signaling pathways activated in bcl-2 over-expressing human Mantle Cell Lymphoma (MCL) cell lines (JVM-2 and Z-138) that have been treated with oblimersen; a molecular gene silencing strategy that effectively suppresses bcl-2 in vitro and in vivo. Co-immuno­precipitation studies clearly indicated that bcl-2 can co-precipitate mdm-2, p27 and cyclin D1a and cyclin D1b. These results provided strong preliminary data of novel interactions leading to the implication that bcl-2 over-expression plays an important role in the maintenance of these cell signaling pathways. 

TAMs Contribute to Tumor Growth

Miselis et al.

Page 788

Tumors are a mixture of neoplastic and host stromal cells which establish a microenvironment that contributes to tumor progression. Miselis and colleagues examined the contribution of tumor-associated macrophages (TAMs) to tumor growth and metastasis using an orthotopic, immunocompetent murine model of diffuse malignant peritoneal mesothelioma. Mice bearing established tumors showed a 2-fold reduction in the number of tumors and relative tumor burden when exposed to half the previous dose of CLIP delivered by repeated i.p. injection. These reductions in tumor burden were statistically significant and identify TAMs as an important host-derived cell that contributes to growth, invasion, and metastasis in diffuse malignant peritoneal mesothelioma. 

Inhibition of EGFR activity with small molecules or antibodies is a new therapeutic modality in the treatment of several forms of cancer. The ability of the EGFR inhibitor Gefitinib (Iressa) to prevent/treat methylnitrosourea (MNU) induced mammary cancers and to modulate biomarkers in female Sprague-Dawley rats was examined by Lubet and colleagues. Treatment with Iressa (10 mg/kg BW/day) continually or intermittently (either "3 weeks on/3 weeks off" or "4 days on/3 days off") reduced cancer multiplicity by 91, 24, and 68%, respectively. However, all regimens reduced tumor weights >85%. Finally, combining suboptimal doses of Iressa with suboptimal doses of Vorozole (an aromatase inhibitor) or Targretin (a RXR agonist) yielded greater chemopreventive efficacy than any of these agents administered alone.

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