American Association for Cancer Research

January 1 2009 Clinical Cancer Research Highlights

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Selected Articles from the January 1, 2009 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 January 1 issue of Clinical Cancer Research.


A Multicenter Phase I/II Study of TLC-D99, Paclitaxel,Trastuzumab in HER-2 Breast Cancer

Cortes et al.

Page 307

Anthracyclines given in combination with the monoclonal antibody trastuzumab are highly clinically active in patients with HER2 breast cancer but result in an increased risk of cardiac dysfunction. To circumvent this problem, Cortes and colleagues decided to explore a less cardiotoxic anthracycline, nonpegylated liposomal doxorubicin (TLC-D99), in combination with the approved trastuzumab plus paclitaxel regimen. In this phase I/II study they found that this combination was very active, with a response rate of 98% and no evidence of treatment-related clinical heart failure. Hence, a nonpegylated liposomal anthracycline may provide the important benefit of anthracyclines and trastuzumab while diminishing the risk of cardiac toxicity, and as a result, a phase III randomized study is under way. 
 

The Molecular Role of Clusterin in Apoptosis

Trougakos et al.

Page 48

Trougakos et al.Secretory clusterin (sCLU) exerts pro-survival activity against most cancer therapies. To explore its molecular function, Trougakos and colleagues designed novel siRNAs targeting sCLU. siRNA-mediated depletion of sCLU in human cancer cells triggered p53-dependent G1-S growth retardation and increased mitochondrial apoptosis. Increased apoptosis was correlated with altered ratios of Bcl-2 protein family members. Also, sCLU was found to stabilize the cytoplasmic Ku70-Bax protein complex, demonstrating that sCLU serves as a cytosol retention factor for Bax. These findings provide novel insight into the molecular function of sCLU and provide further evidence that sCLU is a potential molecular target for tumor therapy.


DPPE Targets Breast Tumor–Initiating Cells

Deng et al.

Page 119

In a phase III randomized trial for metastatic breast cancer using doxorubicin (Dox) with or without DPPE (tesmilifene), addition of DPPE resulted in a significant improvement in overall survival but paradoxically no difference in objective tumor response. Here, Deng and colleagues demonstrate that continuous exposure to pharmacologically attainable doses of DPPE effectively targets breast cancer tumor-initiating cells (TICs), whereas Dox preferentially kills non-TICs. These results identify DPPE as a novel TIC-specific therapeutic and suggest that DPPE-based therapy should involve continuous or frequent administration of the drug. 


Tubulysins are a novel tubulin-targeted class of natural compounds that are highly active in multidrug-resistant cells, but have no therapeutic window due to high toxicity. Schluep and colleagues synthesized a nanoparticle prodrug of tubulysin A, which is designed to release the drug upon endocytosis by cancer cells. Compared to the small molecule analog, tubulysin nanoparticles displayed a 100-fold increase in maximum tolerated dose and significantly increased antitumor activity in animal models of human cancer. These results suggest that macromolecular prodrugs may facilitate the clinical development of this class of compounds. 


Bioluminescence Imaging in Preclinical Models

Zhang et al.

Page 238

Optical imaging technology has the potential to help develop models of metastasis and evaluate the anti-metastatic potential of drugs. Here, Zhang and colleagues applied bioluminescence imaging (BLI) technology to characterize the MDA-MB-435-HAL-Luc subrenal capsule (SRC) and mammary fat pad (MFP) mouse tumor models. Compared to the MDA-MB-435-HAL-Luc MFP model, the SRC model exhibited more efficient, spontaneous metastasis, which significantly affected mouse survival time. BLI allowed quantitative assessment of the anti-tumor and anti-metastatic efficacy of anti-neoplastic agents in both tumor models. These results show that by using an optimized BLI technique, clinically relevant disease models can be developed for evaluating drug effects.  


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