Every year more than 146,000 Americans are diagnosed with colorectal cancer [1], the third most common type of cancer in the United States. It also is the third highest cause of cancer death, killing nearly 50,000 people annually, more than who die each year on the nation?s roadways. This cancer affects men and women in nearly equal numbers.

In patients with stage III colon cancer who have undergone complete resection of the primary tumor or for palliative treatment of metastatic disease in patient with advanced colorectal cancer one of the most commonly used therapies involve combinations of fluoropyrimidines (5FU/LV) and oxaliplatin (Eloxatin?, Sanofi-Aventis), an antineoplastic organoplatinum complex.

Urgent Need
While the drug is often applied in an adjuvant or palliative setting and has shown to improve survival and reduce mortality rate, a significant number of patients experience serious side effects from oxaliplatin treatment, including long-term sensory nerve damage or prolonged neurotoxicity. This creates an urgent need for the development of methods to identify the likelihood of benefit of oxaliplatin therapy designed to guide the optimal use of this drug.

Complexity of Treatment
While the development of targeted therapies, such as cetuximab (Erbitux?, Bristol-Myers Squibb/BMS, Imclone and Merck KGaA), which targets the epidermal growth factor receptor (EGFR), and bevacizumab (Avastin?, Genentech/Roche), which targets the vascular endothelial growth factor (VEGF), offers promise for improved outcomes in colon cancer, these treatments will, no doubt, also increase the complexity of treatment planning for these patients.

Nerve damage, or neurotoxicity, associated with oxaliplatin is most commonly manifest as pain or a loss of sensation in the hands and feet and can severely affect a patient?s quality of life and ability to work. These symptoms are experienced in some form by the majority of patients receiving this drug and, for some patients, can be permanent.

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Progressing developments
In May 2008, Genomic Health Inc. (Redwood City, California) announced results from a study identifying a small number of genes that could predict response to cetuximab. These results, presented during that year?s annual meeting of the American Society of Clinical Oncology (ASCO) [2], suggested that quantitative expression of a number of identified genes used in conjunction with K-RAS mutation status, increases the ability to predict which patients might benefit from colon cancer treatment with cetuximab over K-RAS status alone.

Further research by Genomic Health and the Translational Genomics Research Institute (TGen , Phoenix, Arizona), shows that genomic research may now also help physicians better target oxaliplatin treatment in colorectal cancer patients.

In this study, published online and pending print publication in Molecular Cancer Research [3], researchers examined the role of individual cancer genes to influence the sensitivity or resistance of colon cancer cells grown in laboratory culture. An in vitro cell-based small interfering RNA (siRNA) screen of 500 genes ? with 2,000 unique siRNA sequences ?identified 27 genes that, when silenced, altered the sensitivity of colon tumor cells to oxaliplatin, causing damage to the cancer cells? DNA and inhibiting the cancer cells? ability to reproduce and survive. The same process altered the activity of several signaling nodes, including AKT1 and MEK1. This study also showed that diverse gene networks appear to influence tumor survival in response to DNA damage by oxaliplatin.

?These 27 genes, whose loss of function significantly affect the effectiveness of oxaliplatin, may be promising therapeutic biomarkers for oxaliplatin,? said Dr. Holly Yin, head of TGen?s Cellular Genomics Collaborative Center in Scottsdale, and a co-author of the study.

Dr. Robert J. Pelham, a research scientist Genomic Health and the study?s senior author, said the findings indicate a need for additional clinical studies on tumor specimens in patients treated with oxaliplatin. ?Such future clinical studies could eventually lead to potential clinical applications, where patients could benefit,? Dr. Pelham said.

[1] Colorectal Cancer Facts & Figures 2008-2010 American Cancer Society
[2] Baker JB Dutta D, Watson D, Maddala T, Shak S, Rowinsky EK, Xu L, Clark E, Mauro DJ, . Khambata-Ford S. Evaluation of tumor gene expression and K-Ras mutations in formalin-fixed, paraffin-embedded tumor tissue as predictors of response to cetuximab in metastatic colorectal cancer (abstract 3512). J Clin Oncol 26: 2008 (May 20 suppl; abstr 3512)
[3] Harradine KA, Kassner M, Chow D, Aziz M, Von Hoff DD, Baker J, Yin H, Pelham RJ. Functional Genomics Reveals Diverse Cellular Processes that Modulate Tumor Cell Response to Oxaliplatin. Mol Cancer Res. 2010 Dec 17. [Epub ahead of print]

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