American Association for Cancer Research

January 2008 Molecular Cancer Therapeutics Highlights

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Selected Articles from the January 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 January 2008 issue of Molecular Cancer Therapeutics


CYP1B1 Interferes with Taxane Treatment

Sissung et al.

Page 19

Sissung and colleagues observed that individuals carrying two copies of the CYP1B1*3 polymorphic variant had a poor prognosis after docetaxel-based therapies compared to individuals carrying at least one copy of the CYP1B1*1 allele. The investigators hypothesized that an indirect gene-drug interaction was interfering with the primary mechanism of action of docetaxel, tubulin polymerization. Their studies showed that CYP1B1-mediated metabolism of estrogen could be responsible for indirect interference with the primary mechanism of action of docetaxel through both inhibition of tubulin formation and through the formation of docetaxel adducts, and showed that catechol estrogens also can mediate the interference with the aforementioned mechanism of action of docetaxel.  


Group Biomarkers Detect Ovarian Cancer Early

Tchagang et al.

Page 27

One reason that ovarian cancer is such a deadly disease is because it is not usually diagnosed until it has reached an advanced stage. A mathematical algorithm called “group biomarkers” was used by Tchagang and colleagues to identify co-regulated genes across normal and different stages of cancerous tissues. The genes encoded for secreted proteins and exhibited higher expression levels in ovarian cancer compared to normal ovary and non-ovarian tissues. Unlike prior sets of biomarkers identified by statistical methods, group biomarkers may be involved in pathways related to different types of cancer development and may serve as novel biomarkers in diagnostic tests. 


Anti-angiogenesis Compounds Interfere with Chemotherapy of Gliomas

Claes et al.

Page 71

Treatment with angiogenesis inhibitors (AIs) may be beneficial for patients with high grade glioma, amongst others because AIs induce normalization of tumor vessels, resulting in better perfusion and distribution of chemotherapeutics to tumor cells. A number of phase II trials are ongoing in which AIs are tested in combination with chemotherapy. Claes and colleagues demonstrated that AI-induced normalization of the vasculature in gliomas also implies restoration of the blood brain barrier which is disrupted during angiogenesis, diminishing uptake of chemotherapy. The authors concluded that the use of such compounds in neuro-oncology should be reconsidered, as combination therapy including AIs for brain tumors may be less effective than chemotherapy alone. 


The PRL phosphatases are currently being investigated as potential therapeutic targets in cancer. However, the expression of PRL phosphatases in pancreatic cancer and the effects of PRL protein inhibition in pancreatic cancer cells have not been explored. Stephens and colleagues found that both PRL-1 and PRL-2, but not PRL-3 are potentially overexpressed in pancreatic cancer, and siRNA mediated knockdown of both PRL-1 and PRL-2 was needed to see anti-tumorigenic effects. Their data suggested that all three PRL proteins should be evaluated in future PRL studies, and that PRL phosphatases might perform similar functions upstream of AKT in cancer cells.  


SEMA6A Circumvents TUBB3 Overexpression 

Prislei et al.

Page 233

Overexpression of class III β-tubulin (TUBB3) represents a prominent mechanism of drug resistance in several solid tumors. Prislei and colleagues found a novel pathway linked to the control of TUBB3 expression. TUBB3 expression was either enhanced or inhibited if semaphorin 6 class A (SEMA6A) was stably overexpressed or silenced, respectively. This mechanism was associated with SEMA6A cytoskeletal compartmentalization, in a complex with β-actin. The authors concluded that SEMA6A cytoskeletal signaling function is distinct from the known role as a membrane receptor and provides a novel “druggable” target, useful to circumvent TUBB3 overexpression and the consequent acquisition of the drug resistant phenotype. 


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