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IoM: FDA, Industry Accord Aids Dx-Rx Co-Development


Early biomarker-based research and greater cooperation between the US Food and Drug Administration and the pharmaceutical industry will enhance drug-diagnostic co-development efforts for cancer indications, according to a report issued earlier this year by the National Academies of Science’s Institute of Medicine.

The report, Cancer Biomarkers: The Promises and Challenges of Improving Detection and Treatment, recommends that the federal research agencies create a single entity focused on biomarker development, support cell and tissue repositories for validating new biomarkers, and focus on identifying biomarkers with broad applicability.

It also recommends that FDA and industry come up with new strategies, methods, and infrastructure to “leverage and integrate the available data to better inform the biology.” Since developing a diagnostic together with a therapeutic is costly, the report suggests that FDA and industry should devise strategies to share and minimize the costs and risks of co-development.

“The best example of where having a biomarker made all the difference in the world is with the approval of Gleevec” in Philadelphia-positive chronic myeloid leukemia patients, according to Harold Moses, professor of cancer biology, medicine, and pathology at Vanderbilt University School of Medicine. Moses also chairs IoM’s Committee on Developing Biomarker-based Tools for Cancer Screening, Diagnosis, and Treatment, which authored the report.

Gleevec, which inhibits the Bcr-Abl tyrosine kinase, was approved after Phase II trials. “If you had Bcr-Abl translocation, then there was a better than 90 percent probability that you would respond,” Moses says. “So that’s the hope with the development of other biomarkers and the feeling is with more complex solid tumors you are going to have to look at a panel of biomarkers, not a single one.”

The IoM report acknowledges that validating a companion diagnostic can substantially add to the cost of drug development, making companies unwilling to invest in developing a genetic test without a level of certainty that the drug will garner FDA approval.
— Turna Ray


NIH Dual-Reporter Assay Enhances Precision

Researchers at the National Institutes of Health have published the first cell-based assay run at the NIH National Chemical Genomics center — a two-reporter luciferase-based assay to identify upstream inhibitors of the NFkB pathway that appears to offer a number of advantages over previous methods.

The study, reported in last month’s issue of Assay and Drug Development Technologies, describes a two-reporter luciferase-based assay that uses red and green click-beetle luciferases to identify stabilizers of the IkBa protein in the lymphoma cell line OCI-Ly3.

According to Eric Davis, a senior research fellow at the Metabolism Branch of the National Cancer Institute and lead author of the paper, the dual-reporter format offers several advantages over single-reporter assays and previous two-color assays, including enhanced precision and the exclusion of nonspecific transcriptional effects.

In addition, the assay lends itself well to a high-throughput screening format. The NIH researchers validated their protocol in a 1,536-well format to screen more than 2,600 bioactive compounds and note in the paper that they have used the assay to screen 66,000 compounds in a study “to be published in a future report.”

“We wanted something that would specifically report on the biology of the lymphoma cells that we used, which for our purposes was the green beetle luciferase-IkBa fusion,” says Doug Auld, group leader for genomic assay technologies at the NCGC and a co-author on the paper. 

Auld says that the dual-reporter design helped uncover an unexpected number of nonspecific signal activation events that would have gone unnoticed in a single-color assay.

“Although this has been reported before in the literature, we weren’t anticipating as many as we saw here,” he says. “The ratiometric nature of this assay allowed us to flag them immediately.”

Auld notes that a one-reporter system would have yielded a number of false positives, which “would have been a real problem.”
— Charlotte LoBuono


Short Reads

Tripos will not sell its Discovery Research business to Provid Pharmaceuticals, according to a Securities and Exchange Commission filing. Tripos told Provid it had terminated the stock purchase agreement the companies signed in January, which had hinged on whether or not Provid could gather the necessary financing.

The Mount Sinai Medical Center in New York will use a $12.5 million donation from a regional foundation to establish a research center to study personalized medicine. Mount Sinai will use the funds to start the Charles Bronfman Institute for Personalized Medicine.

Through its ToxCast program, the US Environmental Protection Agency issued contracts to Caliper Life Sciences as well as Cellumen for multi-year toxicity projects. Caliper said the EPA hired its NovaScreen Biosciences to help predict how chemicals such as pesticides will interact with the environment, humans, and animals. Cellumen said it will use its cytotoxicity profiling method to test chemicals that may be harmful to humans.

In a partnership agreement, Invitrogen will screen Emiliem’s multi-kinase inhibitors. The two-phase agreement calls for Invitrogen to confirm specificity and potency of Emiliem’s compounds, to study the effects of these compounds on biological pathways, and to use metabolizing liver enzymes to determine profiles of lead molecules.

Roche Diagnostics will work with Swiss nonprofit Foundation for Innovative New Diagnostics to study the potential uses of in vitro diagnostics for what it calls poverty- related diseases such as tuberculosis, sleeping sickness, and malaria. The nonprofit agency is funded by the Bill & Melinda Gates Foundation, the US Agency for International Development, the European Union, and the Dutch government.

PerkinElmer acquired UK imaging company Improvision, which makes 3D and 4D cellular-imaging software and hardware. PerkinElmer says the acquisition will build on the high-content screening platform it got when it purchased Evotec Technologies.

Novartis hired Warnex to perform bioanalytical and pharmacogenetic services for the drug maker’s leukemia and intestinal tumors program. Warnex says its program will use liquid chromatography and mass spec technologies to test blood levels of Novartis’ drug Gleevec to track non-adherence or suboptimal dosing.

NimbleGen will help Upstream Biosciences validate biomarkers by providing lab services such as whole-genome chromatin immunoprecipitation arrays to validate in silico binding-site predictions.

Promega and China’s Guangzhou Institute of Biomedicine and Health plan to co-develop drug-screening assays for cytochrome P450, kinase, and GPCR profiling.



US Patent 7,191,068. Proteomic analysis of biological fluids. Inventors: Ron Rosenfeld, Sri Nagalla, and Mike Gravett. Assignee: Proteogenix. Issued: March 13, 2007.

This invention “concerns the identification of proteomes of biological fluids and their use in determining the state of maternal/fetal conditions, including maternal conditions of fetal origin, chromosomal aneuploidies, and fetal diseases associated with fetal growth and maturation.”

US Patent 7,184,893. Method for selecting an optimally diverse library of small molecules based on validated molecular structural descriptors. Inventors: Richard Cramerand Robert Clark. Assignee: Tripos. Issued: February 27, 2007.

This patent covers the “use for biological screening purposes of a subset (library) of a large combinatorially accessible chemical universe [to increase] the efficiency of the screening process only if the subset contains members representative of the total diversity of the universe,” according to the abstract.

US Patent 7,177,767. Systems and methods for the detection of short and long samples. Inventors: Vladimir Ostoich, Kenneth Aron, and Dennis Bleile. Assignee: Abaxis. Issued: February 13, 2007.

The patent relates to methods and systems for “detecting the accidental use of short and long samples in the clinical analysis of a sample, specimen, or assay. The systems can include a clinical analyzer for determining one or more values for one or more measurable characteristics of a sample.”

US Patent 7,202,086. Method for massive directed mutagenesis. Inventors: Marc Delcourt and Stephane Blesa. Assignee: Biomethodes. Issued: April 10, 2007.

This patent covers “a method of high-rate directed mutagenesis, that is the formation of numerous directed mutants in reduced time and with reduced number of steps. Said method is therefore referred to as massive mutagenesis.”


Data Points

$6.6 million

Now that Stratagene has been acquired by Agilent Technologies for $246 million, the company’s CEO Joseph Sorge announced plans to form a new entity that will pay $6.6 million for some of Stratagene’s molecular diagnostics assets.

$1 million

Amount raised by Motif Biosciences, a population-genetics company focusing on links to diseases prevalent in populations in the Persian Gulf region, in a series C financing that will help pay for research into type 2 diabetes and asthma.

The Scan

Study Examines Insights Gained by Adjunct Trio RNA Sequencing in Complex Pediatric Disease Cases

Researchers in AJHG explore the diagnostic utility of adding parent-child RNA-seq to genome sequencing in dozens of families with complex, undiagnosed genetic disease.

Clinical Genomic Lab Survey Looks at Workforce Needs

Investigators use a survey approach in Genetics in Medicine Open to assess technologist applications, retention, and workforce gaps at molecular genetics and clinical cytogenetics labs in the US.

Study Considers Gene Regulatory Features Available by Sequence-Based Modeling

Investigators in Genome Biology set sequence-based models against observational and perturbation assay data, finding distal enhancer models lag behind promoter predictions.

Genetic Testing Approach Explores Origins of Blastocyst Aneuploidy

Investigators in AJHG distinguish between aneuploidy events related to meiotic missegregation in haploid cells and those involving post-zygotic mitotic errors and mosaicism.