American Association for Cancer Research

June 2007 Molecular Cancer Therapeutics Highlights

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Selected Articles from the June 1, 2007 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 June 2007 issue of Molecular Cancer Therapeutics


EMT Predicts Gefitinib Resistance

Frederick et al.

Page 1683

The modest response of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung carcinoma (NSCLC) patients to epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib indicates the need for the development of biomarkers to predict response. Frederick et al. determined gefitinib sensitivity in a panel of HNSCC cell lines by a 5-day MTT assay and confirmed these responses with analysis of downstream signaling by immunoblotting and cell cycle arrest. Common markers of resistance between the two tumor types included genes associated with the epithelial to mesenchymal transition (EMT). The authors’ data support a role for EMT in establishing gefitinib resistance for both HNSCC and NSCLC and indicate that clinical trials should address whether these biomarkers will be useful for patient selection.
 

Optical Fluorescence Images Myeloma Cells

Oyajobi et al.

Page 1701

Recent advances have led to the emergence of several potential therapies for myeloma. However, determining which agents to move into clinical development has been challenging because of the lack of pre-clinical models of the disease in which anti-tumor efficacy can be objectively and reliably evaluated. Oyajobi et al. modified the Radl 5T model of myeloma bone disease and showed that GFP-expressing 5TGM1 myeloma cells can be imaged in the mouse skeleton spatio-temporally. Utility of the model as a practical, rapid and sensitive means of assessing anti-tumor activity of potential therapeutics was validated in tumor-bearing mice treated with the proteasome inhibitor, Bortezomib. Whole-body fluorescence imaging may facilitate high throughput in vivo screening to identify efficacious novel anti-myeloma agents for drug development.


Sulindac and LC-1 Suppress Pancreatic Tumor Growth

Yip-Schneider et al.

Page 1736

Novel therapies are needed to improve treatment options for pancreatic cancer. Two targets of recent interest known to be upregulated in pancreatic cancer are nuclear factor kappaB (NF-κB) and cyclooxygenase (COX). The COX inhibitor sulindac and LC-1, a bioavailable pro-apoptotic drug associated with NF-κB inhibition, were evaluated in a xenograft model of human pancreatic cancer. Yip-Schneider et al. found that sulindac alone or in combination with LC-1 suppresses pancreatic tumor growth in vivo, correlating with inhibition of cyclin D1 expression. Thus, these agents demonstrated therapeutic efficacy, and cyclin D1 may be an important determinant of response to therapy.


Diffuse brain invasion remains the most challenging issue for successful glioma therapy. By employing an ex vivo tumor implantation model, Coras et al. identified the PPAR-γ activator troglitazone as a potent drug to block glioma cell migration and brain infiltration. This anti-migratory property is PPAR-γ independent and could be attributed to transcriptional repression of TGF-β and reduced TGF-β release. Due to its capacity to counteract TGF-β signalling at clinically achievable doses, troglitazone and its derivatives may be considered for adjuvant therapy of malignant gliomas and other highly migratory tumor entities.


Oral Filarasib Shows Potential Against Lung Cancer

Zundelevich et al.

Page 1765

Lung cancer is the leading cause of cancer-related deaths. Despite advances in surgery, chemotherapy and radiotherapy, survival rates have hardly changed in the last decade, and long-term survival rates remain extremely poor. Zundelevich et al. showed that the Ras inhibitor farnesylthiosalicylic acid (FTS, filarasib) inhibits proliferation of human lung cancer cells in vitro and that orally formulated filarasib inhibits lung cancer tumor growth in a nude mouse model. These results suggested that oral filarasib may be considered as a potential treatment for lung cancer therapy.


Aurora Kinase Inhibitor Alters Leukemia Cells

Ikezoe et al.

Page 1851

Aberrant expression of Aurora kinases occurs in solid tumors and is associated with aneuploidy and carcinogenesis. Ikezoe et al. found in this study that Aurora kinase A and B were aberrantly expressed in variety types of human leukemia cell lines as well as freshly isolated leukemia cells from individuals with acute myeloid leukemia. ZM447439, a novel selective Aurora kinase inhibitor, induced growth inhibition, caused accumulation of cells with 4N/8N DNA content and mediated apoptosis of human leukemia cells as measured by thymidine-uptake, cell cycle analysis, and annexin V staining, respectively. However, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy normal volunteers. Thus, inhibition of Aurora kinases may be a promising treatment for individuals with leukemia.