Genetic Engineering & Biotechnology News

JUN15 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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26 | JUNE 15, 2018 | Genetic Engineering & Biotechnology News | Terence Rhodes, M.D., director of immuno-oncology at Utah-based Intermountain Healthcare, thinks that Tumor Mutational Burden (TMB), or the number of mutations in a tumor, is starting to come of age as a biomarker that can predict which patients will respond best to immunotherapy. "TMB is a byproduct that has evolved out of precision genomics and next-generation sequencing that has already been established in the oncology world," he says. In TMB, sets of 150–300 genes were examined from cancer patients. The particular genes that comprised each set depended on the company that made the assay. But it almost doesn't mat- ter, he says, as doctors started correlating TMB, i.e., the num- ber of mutations rather than a specific type of mutation that respond to immunotherapy. "If there is a high TMB, the chances of immunostimula- tory antigens being expressed on the outside of tumor cells increase," he explains. Astonishingly, TMB is a better predic- tor of response to PD-1 inhibitors like Keytruda ® (Pembro- lizumab) and Opdivo ® (Nivolumab) than to the presence of PD-1. Since PD-1 is detected via immunohistochemistry and it is such an imperfect marker (patients without it can still respond to anti-PD-1 therapy), Dr. Rhodes believes that it will soon fall out of favor. "In terms of NGS applications in drug discovery and de- velopment, NGS can be used to understand disease biology and to target key pathways driving the disease. It can also be useful in uncovering mechanisms associated with drug resistance and rational drug combinations," according to Prashun Mishra, Ph.D., founder and CEO of Agility Phar- maceuticals. "Moreover, NGS-based gene panels can be used as companion diagnostics assays." Tropomycin receptor kinase (TRK) fusion genes and fi- broblast growth factor receptor 2 (FGF-R2) are druggable targets that were identified through NGS, and a number of companies are now searching for drugs to target them, adds Dr. Mishra. NGS can facilitate high-throughput screens of chemical libraries and small molecules: Each molecule in the library can be tagged with a unique identifying oligonucle- otide. This makes determining which ones bind to the target NGS a relatively simple endeavor. Understanding Drug Resistance NGS has also uncovered the mechanism behind the de- velopment of drug resistance, an inevitability in a disease as Artistic representation depicting how targeted therapies are applied in precision medicine for cancer. These panels are on display as an art installation at the Intermountain Precision Genomics headquarters in St. George, UT. Translational Medicine Molecular Diagnostics Brings Patients Hope Diana Gitig, Ph.D. Next-generation sequencing (NGS) platforms, along with immunotherapies like checkpoint inhibitors, have brought the promise of precision medicine for cancer patients closer to reality. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) is a major tool for diagnosing genetic mutations from blood and other body fluids, but the technology can be expensive. NGS, and, by extension, liquid biopsies, can be op- timized by incorporating quality control steps during library preparation. Performing quality control on nucleic acid samples lets users identify degrad- ed, fragmented, and low-purity samples that are likely to produce suboptimal libraries and yield poor sequencing per- formance, saving researchers time and money. Illumina has integrated Advanced Analytical Technologies' (AATI) pri- mary nucleic acid quality control plat- form, the Fragment Analyzer, into its NGS library prep workflows. The instru- ment has two major advantages over traditional chip-based systems, notes Brian Bodemann, Ph.D., an AATI account manager. First, it can accurately quantify nu- cleic acids, he explains. Wrong concen- trations of certain molecules can have disastrous results. If the adaptor stoichi- ometry is off and proper clean up steps are not completed, for example, adap- tors can form strings of repetitive DNA sequences that can bind to the flow cell and stymie data collection. "This will cause a $10,000 sequencing run to produce poor data," says Dr. Bode- mann. "If the problem goes unnoticed, this can affect the sequencing data quality from all the other samples," add- ing that the Fragment Analyzer can flag these low-quality samples and prevent them from slowing down sequencing. The instrument also qualifies cfDNA more effectively, maintains Dr. Bode- mann. On chip-based systems, high molecular weight (HMW) contaminating DNA may not fully separate from the common nucleosomal peaks. Because the Fragment Analyzer uses capillary electrophoresis, any HMW DNA can be fully separated from cfDNA. "By providing accurate quantification and qualification of the nucleosomes, the Fragment Analyzer provides scien- tists with a simpler, faster and more eas- ily interpretable route to results," says Dr. Bodemann. "Every moment you spend trouble- shooting your sequencing data is time you're wasting on making patients and doctors wait for results." n Quality Control of Cell-Free DNA for Next-Gen Sequencing

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