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TGen, Genomic Health ID Potential Oxaliplatin Response Genes; Findings May Enhance Colon Cancer Test

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By Turna Ray

A preliminary study conducted by Genomic Health and the Translational Genomics Research Institute suggests that certain genes may help explain why colon cancer patients have varying responses to the commonly prescribed chemotherapeutic oxaliplatin.

The results of this trial, if confirmed in additional studies, may help Genomic Health add a treatment benefit indication to its Oncotype DX test for colon cancer.

An in vitro cell-based small-interfering RNA screen of 500 genes, representing 2,000 unique siRNA sequences, found 27 genes that, when silenced, affected the sensitivity of colon tumor cells to oxaliplatin. Specifically, these 27 loss-of-function genes caused "damage to the cancer cells' DNA and inhibited the cancer cells' ability to reproduce and survive," the researchers said in a statement announcing the results from this investigation.

The siRNA screening study was published in Molecular Cancer Research and led by Genomic Health scientist Robert Pelham.

"Silencing of a group of putative resistance genes increased the extent of oxaliplatin-mediated DNA damage and inhibited cell cycle progression in oxaliplatin-treated cells," the researchers state in the paper's abstract. "The activity of several signaling nodes, including AKT1 and MEK1, was also altered."

The researchers used cDNA transfection to over-express LTBR and TMEM30A, genes that were identified in the siRNA screen as mediators of oxaliplatin sensitivity. "In both instances, over-expression conferred resistance to oxaliplatin." Additionally, the researchers found that "diverse" gene networks may also be implicated in oxaliplatin's efficacy on colon tumors.

"Those genes whose loss of expression (or function) is related to oxaliplatin sensitivity may be promising therapeutic targets to increase patient response to oxaliplatin," Pelham and colleagues wrote in the Molecular Cancer Research study.

Although these 27 genes "may be promising therapeutic biomarkers for oxaliplatin," the researchers emphasized that additional studies must be conducted before these potential response markers may be clinically applicable.

Genomic Health, having developed formalin-fixed paraffin-embedded tissue-based assays for the genes identified in the study with TGen, is planning "to initiate studies this year on tumor specimens in patients who were treated with oxaliplatin to examine whether the genes identified in the Pelham study or other candidate genes can predict the likelihood of oxaliplatin benefit."

Results from these additional studies may be used by Genomic Health to further enhance its Oncotype DX test for colon cancer, which is currently used to gauge which stage II colon cancer patients are likely to experience disease recurrence.

"We would expect that new genes would be added that predict oxaliplatin [response]," Steve Shak, Genomic Health's chief medical officer, told PGx Reporter. "We also would expect that the 12-gene Recurrence Score would also be needed for treatment planning since assessment of the likely absolute benefit of chemotherapy depends on both recurrence risk and prediction."

In 2009, Genomic Health reported that the landmark QUASAR validation study for its colon cancer test met its primary endpoint to predict the likelihood of post-operative disease recurrence in patients with stage II disease. However, the test did not meet a second endpoint using a set of genes to predict which patients are likely to benefit from post-operative 5-fluorouracil/leucovorin treatment (PGx Reporter 04/15/09).

Last year, the company told investors that it was working on building the clinical evidence to support the test's use to predict oxaliplatin benefit. Officials said last September that the company was planning to introduce the treatment benefit indication for Oncotype DX colon cancer by the end of 2010 (PGx Reporter 09/29/10).

In stage II colon cancer, between 75 percent and 80 percent of patients will benefit from surgery alone, while between 20 percent and 25 percent will see their cancer recur. Meanwhile, between 3 percent and 4 percent will benefit from chemotherapy.

Oxaliplatin is readily used to treat colon cancer, often in the treatment of early cancer after a patient has had surgery to reduce the chances of recurrence. The drug is also used to treat advanced stage disease to slow metastasis.

However, given the number of serious toxicities that patients experience following oxaliplatin treatment, there is an "urgent need to identify genes that are responsible for drug sensitivity or resistance, which results in directing therapy to those most likely to benefit," the study authors wrote in Molecular Cancer Research.


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