Category Archives: Pharmacogenomics

By Turna Ray

CHICAGO A recent analysis of genotype and clinical data from more than 700 heart failure patients found that individuals who are homozygous for the wild-type allele Ser49 in the beta 1-adrenergic receptor gene experienced prolonged survival when they received treatment with beta-blockers compared to Ser49 homozygotes who didn't receive such treatment.

The study, led by researchers from the University of North Carolina, Chapel Hill, also found that carriers of one or two copies of the Gly49 allele in the beta1-AR gene did not experience a survival advantage when treated with beta-blockers compared to Gly49 carriers who didn't receive such drugs.

Beta-blockers inhibit beta-adrenergic substances that regulate the nervous system of the heart and are often prescribed to control high blood pressure, to manage irregular heart rhythms, and to treat heart failure patients. There are several beta-blockers on the market approved by the US Food and Drug Administration, including AstraZeneca's Toprol XL and GlaxoSmithKline's Coreg.

Based on data from past studies, UNC researchers Jasmine Talameh, Kirkwood Adams, and others hypothesized that Ser49 allele status "will be associated with beta-blocker survival benefit in a large, heterogeneous, US heart failure population," said Talameh, who presented data from this study at the American College of Cardiology meeting here this week.

Study investigators reviewed beta-blocker use and survival for heart failure patients enrolled in the United Investigators to Evaluate Heart Failure Biomarker Registry from 2000 to 2002. The current analysis involves more than 700 patients in the registry for whom there was information on beta-blocker use, survival, and genotype.

"The UNITE-HF DNA Registry was started by Kirkwood in 1999 as a way to promote clinical registry, biomarker, and genomic research in heart failure," Talameh said during her presentation. "These prospective, multicenter, observational registries were designed to study medication use, long-term outcomes, and the genomics of heart failure patients seen in US heart failure specialty clinics."

Patients in the registry had a history of heart failure and could have been asymptomatic at the time they were enrolled. According to Talameh, the majority of patients in the registry had received Coreg and Toprol.

Study investigators used mass spectrometry to genotype patients for the Gly49 and Ser49 alleles in the lab of Howard McCleod, director of UNC's Institute for Pharmacogenomics and Individualized Therapy. During the follow-up period, researchers collected patients' clinical information at the study sites and then periodically with the Social Security Death Index.

Among the study participants, 68 percent were Ser49 homozygous and 32 percent were Gly49 carriers. Using the Social Security Death Index, researchers found that more than 340 patients died after an average follow up of seven years, of which 52 percent were Gly49 carriers and 47 percent were Ser49 homozygous.

More:
UNC Analysis Finds Beta1-AR Alleles Impact Survival in Patients Treated with Beta-Blockers

The Broad Institute and Sanger Institute announced yesterday (March 28) details from their separate cancer cell line databases, the largest such repositories of genomic and drug profiling data to date. With preliminary results published in two Nature papers, the databases should help researchers identify which drugs to use against which cancers to streamline drug development efforts.

This continues to move us towards cancer being understood as a molecular disease instead of an anatomical disease, said Eileen Dolan, who studies pharmacogenomics at the University of Chicago and was not involved in either study. It will help us understand our existing drugs, as well as new drugs, to make more informed decisions in phase I and phase II trials.

In recent years, researchers have become increasingly aware that whether a tumor will respond to a given drug treatment depends on its genomic profile. But because of the vast number of cell lines and variety of drug options, researchers in smaller labs often dont have the resources to identify the best fit for the cancer type or drug theyre studying.

For any variety of cancer drugs that are being developed, we cant necessarily know in advance which cancers are going to be vulnerable, said Levi Garraway, a cancer biologist at the Dana Farber Cancer Institute who spearheaded the Broad project. If you have a large collection of cell lines that are deeply annotated genetically and molecularly, you can probe the biology linked to many types of genetic alterations of interest.

Four years ago, Garraway and his colleagues began a massive screen of 947 cancer cell lines, sequencing cancer-associated genes, profiling drugs, collecting RNA expression data using microarrays, and combing the cancer genomes for repeated regions. And they werent too far along when they learned of a parallel project at the Sanger Institute, led by genomicist Mathew Garnett.

The projects arent identical; they screen different genes and different drugs using slightly different methods. For this reason, Garnett views the two databases as complementary. There was sufficient non-overlap that it was possible to make different observations, agreed Garraway. (See table for details.)

Plus, having two separate databases rather than pooling the data, as previous databases have done, could lend more weight to certain findings. I think having two independent resources is a good thing, said Jian Ma, a computational genomicist at the University of Illinois, who did not participate in the research. If two different groups have the same result for one cell line, it would be more reliable.

The two Nature papers, submitted as a pair, describe how the data for each project were collected, and include confirmatory experiments to demonstrate how the databases could enhance cancer drug development. Garnetts project, called the Cancer Cell Line Encyclopedia, identified a mutation in Ewings sarcoma cells that is highly sensitive to PARP inhibitors, for example. Meanwhile, Garraways database, the Genomics of Drug Sensitivity in Cancer project, includes data suggesting that MEK inhibitors, a class of cancer drugs that target the RAS oncogene, may have increased efficacy in cancers with a mutation in another gene, AHR.

The ultimate hope is that the databases will be used to help people with cancer by better matching a cancer type to a drug, and identifying which patients to enroll in clinical trials based on their genetic flavor of cancer. Often, drugs fail [in clinical trails] simply because theyre not tested in the right people, said Garnett. A better understanding of how drugs respond to genetic mutations, helped by the databases, could help clinicians single out what populations are most likely to respond.

Continued here:
Collecting Cancer Data

The annual meeting of the American College of Cardiology held this week in Chicago featured a number of pharmacogenomically guided studies related to treatments for cardiovascular disease.

The following is a roundup of some of the meeting's pharmacogenomics highlights.

Lack of Association in SLCO1B1 Polymorphisms and Clinical Myalgia after Crestor Treatment

Researchers led by Jacqueline Suk Danik from Brigham and Women's Hospital investigated whether individuals who are carriers of SCLCOB1 rs4363657C and rs4149056C have increased incidence of myopathic complaints when taking AstraZeneca's Crestor (rosuvastatin) compared to non-carriers. In past studies, researchers have seen a similar influence in patients taking Merck's Zocor (simvastatin).

Danik et al. retrospectively genotyped patients receiving Crestor in the JUPITER trial. The original study randomized 4,400 people without heart disease or diabetes to Crestor or placebo. "Among those allocated to active rosuvastatin, there was no difference in [the] rate of myalgia among carriers of the rs4363657C allele or the rs4149056C allele when compared to non-carriers," the researchers found. The researchers had similar findings even after expanding their definition of myalgia to include complaints of muscle weakness, stiffness, or pain.

"In contrast to data for simvastatin, there appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C allele or the rs4149056C allele in the SLCO1B1 gene," Danik et al. concluded.

AstraZeneca, the National Cancer Institute, and the National Heart, Lung, and Blood Institute provided funding for this study.

Impact of CYP2C19 and CYP3A5 Genotypes in Patients Undergoing Stent Procedures, Treated with Maintenance Dose Plavix

Studies have shown that patients with high platelet reactivity after being treated with Bristol-Myers Squibb's Plavix (clopidogrel) may be at increased risk of stent thrombosis after undergoing a stent procedure. Researchers led by Tadasuke Chitose of Kumamoto University examined CYP2C19 and CYP3A5 genotypes, as well as platelet aggregation, in 62 patients. Platelet reactivity was measured twice, after patients received a loading dose (300 mg/day) of Plavix, and then after they received a maintenance dose (75 mg/day) of the drug.

In the study, 31 percent, 42 percent, and 27 percent of patients were extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively. After patients received 300 mg/day of Plavix, platelet reactivity was 4,069 +/-1,383; 4,407 +/-1,755; and 5,301 +/-807 AU*min in the extensive, intermediate, and poor metabolizer groups, respectively. After receiving the maintenance dose of Plavix, platelet reactivity levels were 2,948 +/-1,427; 3,068 +/-1,656; and 4,465 +/-1,557 AU*min in the extensive, intermediate, and poor metabolizer groups, respectively.

See more here:
PGx Highlights from American College of Cardiology Annual Meeting

VOL. 127 | NO. 62 | Thursday, March 29, 2012

Mike Murphy Builders LLC has filed a construction loan for three lots in Germantowns Enclave planned development, phase 3, through Financial Federal Savings Bank for $1.1 million. The sizes of the financed lots are 6,759 square feet fronting Enclave Hollow Lane East, 7,032 square feet fronting Terrene Lane and 6,760 square feet fronting Enclave Green Lane West.

Enclave phase 3 is on the north side of Wolf River Boulevard northwest of the dead end of Forest Hill-Irene Road. The plat was originally filed with the Shelby County Register of Deeds in 2008. It shows 50 lots on about 16 acres.

Source: The Daily News Online & Chandler Reports

Daily News staff

A Sterne, Agee & Leach analyst on Wednesday upgraded shares of First Horizon National Corp., parent company of First Tennessee Bank, saying the regional banks loan portfolio is stabilizing and it may return more money to shareholders this year.

Todd Hagerman lifted his rating on First Horizons shares to Neutral from Underperform.

Shares of the Memphis-based bank closed at $10.48 on Tuesday, and have nearly doubled since hitting a 52-week low of $5.38 on Oct. 4.

Still, Hagerman sees limited potential for the shares to rise significantly. The benefit to the bank from improving credit trends will moderate this year and next year, he said. He kept intact his 2012 and 2013 earnings estimates.

The Associated Press

Continue reading here:
Perkins Chain Hires New CEO

VOL. 127 | NO. 62 | Thursday, March 29, 2012

Mike Murphy Builders LLC has filed a construction loan for three lots in Germantowns Enclave planned development, phase 3, through Financial Federal Savings Bank for $1.1 million. The sizes of the financed lots are 6,759 square feet fronting Enclave Hollow Lane East, 7,032 square feet fronting Terrene Lane and 6,760 square feet fronting Enclave Green Lane West.

Enclave phase 3 is on the north side of Wolf River Boulevard northwest of the dead end of Forest Hill-Irene Road. The plat was originally filed with the Shelby County Register of Deeds in 2008. It shows 50 lots on about 16 acres.

Source: The Daily News Online & Chandler Reports

Daily News staff

A Sterne, Agee & Leach analyst on Wednesday upgraded shares of First Horizon National Corp., parent company of First Tennessee Bank, saying the regional banks loan portfolio is stabilizing and it may return more money to shareholders this year.

Todd Hagerman lifted his rating on First Horizons shares to Neutral from Underperform.

Shares of the Memphis-based bank closed at $10.48 on Tuesday, and have nearly doubled since hitting a 52-week low of $5.38 on Oct. 4.

Still, Hagerman sees limited potential for the shares to rise significantly. The benefit to the bank from improving credit trends will moderate this year and next year, he said. He kept intact his 2012 and 2013 earnings estimates.

The Associated Press

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By Molika Ashford

Genoptix, the medical laboratory within Novartis's molecular diagnostics unit, has launched a targeted sequencing-based test for mutations in BRAF, NRAS, and c-KIT to help physicians tailor treatment for metastatic melanoma patients.

The NexCourse Melanoma sequencing profile, offered through Genoptix's CLIA lab, is the company's first sequencing-based test service and is already being ordered by physicians, according to the firm. Genoptix's President Tina Nova declined to provide details on how the test is being used so far but did tell PGx Reporter in an e-mail that the panel is not being used to place patients into clinical trials for Novartis drugs.

The company sees the service as a tool to help inform treatment decisions for patients with metastatic melanoma by screening for clinically relevant mutations in three genes associated with different prognoses and potential responses to targeted treatments.

However, the NGS profile is "not intended as a test for any specific drugs;" is not linked to any drugs in Novartis' pipeline targeting BRAF, NRAS or c-KIT mutations; and the company is not using the NGS profile to place patients into clinical trials involving drugs in development, "nor do we have any plans to do so," Nova wrote.

And although the service will assess BRAF mutations including V600E and V600K mutations it is not intended to guide treatment with Roches Zelboraf, which is indicated for BRAF V600E mutation-positive metastatic melanoma. The US Food and Drug Administration approved the drug in August alongside Roche's internally developed companion test, the Cobas 4800 BRAF V600 Mutation Test.

"Our focus in Genoptix is on providing physicians with the most relevant clinical information. We believe that NGS technology is going to factor heavily in the diagnosis and treatment of patients in the future," Nova said.

Novartis acquired Genoptix in January 2011 and the business falls within Novartis Molecular Diagnostics, a unit formed around three years ago. The primary focus of the Novartis MDx business is companion diagnostics, but the company is also pursuing a "complementary diagnostics" strategy, which includes tests that don't require extensive coordination between drug and diagnostic development arms or simultaneous drug/test approval by the FDA (PGx Reporter 12/7/2011).

Nova did not detail Genoptixs hopes for the testing service beyond offering a more comprehensive test than currently available single-gene assays to help physicians tailor treatment for each patient.

"The NGS profile provides us with a much more comprehensive picture of the tumor than with assays that target specific point mutations, she said.

Continue reading here:
Genoptix Says NGS Melanoma Test Will Not Be Used to Place Patients in Trials for Parent Novartis