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PGx Highlights From 2007 AACR Annual Meeting

Researchers Discover Molecular Predictors of Drug Response to Breast Cancer Drugs Lapatinib, CI-1040
Researchers at Lawrence Berkeley National Laboratory have identified gene expression signatures that could predict how patients will respond to GlaxoSmithKline’s breast cancer drug lapatinib (Tykerb), a dual inhibitor of EGFR and ErbB2, and CI-1040, a MEK enzyme inhibitor.
“Their findings could help in individualizing treatments for women, and their methodologies could aid in identifying similar biomarkers for responses to other drugs and for other types of cancer,” the American Association for Cancer Research said last week.
Researchers at the LBNL have evaluated a panel of 50 breast cancer cell lines; each cell line represents a single variant of the genetic abnormalities found among breast cancers. “They measured molecular profiles of each cell line and used these to identify subsets of cell lines that represent the subtypes observed in analyses of primary tumors,” AACR said.
For Lapatinib, the strongest association with response was amplification and over-expression of ErBB2. For CI-1040, changes in the MEK pathway were most strongly correlated with response. According to the study authors, combinations of molecular correlates of response were able to quantitatively predict individual cell line responses.
These findings suggest that “the molecular markers can guide the use and testing of other approved and experimental drugs,” one study author said. “This is important since it is logistically and financially impossible to test all of the experimental medicines in each cancer subtype. This ‘systems’ approach suggests a way to prioritize drugs for use in patients and for initial clinical tests.”

French Scientists Link KRAS Mutation to Lack of Response to Cetuximab Treatment
Mutations in the KRAS oncogene could predict patients’ response to Bristol-Myers Squibb’s Erbitux (cetuximab) in patients with colorectal tumors.
“For those with the mutations, the drug is likely to be inefficient and possibly harmful,” researchers at France's Institut National de la Sante et de la Recherche Medicale (INSERM) found.
Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor and is used to treat metastatic colorectal cancer.
The INSERM study enrolled 114 patients treated with cetuximab in combination with Pfizer’s Camptosar (irinotecan).
In the study, approximately 30 percent of patients had a poor response to the drug. In addition, none of the patients who responded to therapy had an activating KRAS mutation. Comparatively, 35 percent of the patients who had stable disease or 55 percent of the patients with progressive disease did have an activating KRAS mutation.
Additionally, researchers noted that the KRAS mutations were independent of another predictive marker of cetuximab response, skin toxicity. In the study, patients with skin toxicity and without a KRAS mutation had a median survival is 15.6 months. However, median survival decreased to 5.6 months when patients had the mutation, but no skin toxicity.

Vanderbilt Researchers Study Impact of TK-Inhibitors Plus Radiation on Lung, Brain Cancer
Researchers at Vanderbilt University are using a biomarker library of peptides to determine if tyrosine kinase inhibitor drugs, combined with radiation therapy, are effective against lung or brain cancer.
This new method for determining biomarkers could “allow physicians to personalize lung or brain cancer therapy and lower the risk of unnecessary radiation treatments,” AACR said in a statement.
Vanderbilt researchers screened lung and brain tumors to determine which peptides were active in the tissue around the tumors and created the library. Using the library, researchers selected peptides that bind to tumors that respond to radiation and TK-inhibitor combination therapy, but not to tumors that do not respond to therapy.
Using this method, researchers uncovered 44 peptides that serve as biomarkers for response to therapy, and that might also help uncover new cancer treatments.

TGen Researchers, GSK Discover Genetic Predictors for Tykerb Response
The Translational Genomics Research Institute and GlaxoSmithKline have discovered through genetic analysis gene markers “by the dozens,” which can be associated to patients’ drug response.  
According to AACR, the TGen researchers found 164 genes involved in regulating the sensitivity of squamous cell head and neck cancer cells to GSK’s Tykerb (lapatinib). Tykerb is approved for metastatic breast cancer.
Researchers evaluated 7,000 genetic targets in human head and neck cancer cells to discover specific genes that might impact an individual's response to Tykerb, an enzyme inhibitor that stops the growth of solid tumors by blocking ERBB2 and EGFR receptors. “However, molecular mechanisms within the cell, largely determined by genetics, could determine how effective cancer drugs are for a particular recipient,” one study author said.
The TGen researchers are currently “refining their genetic ‘hits’ and learning more about how cancer-specific variations in these sensitizing genes might further affect Tykerb response,” AACR said.

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