Genetic Engineering & Biotechnology News

APR15 2017

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16 | APRIL 15, 2017 | GENengnews.com | Genetic Engineering & Biotechnology News however, one mitochondrial and one cyto- solic, was lethal in cell culture, but could be fully rescued by media supplementation with formate or thymidine. "With the knockout of both genes, the ability of cancer cells to utilize serine for its metabolic needs is greatly reduced. When cells with both genes deleted are injected into immune-compromised mice, there is no tu- mor growth; deleting just one of these genes still allows for tumor development and pro- liferation. This is surprising because the dou- ble-knockout cells would grow in culture, but not as a xenografted tumor." "Employing metabolomic profiles of cells as an approach to discover drugs worked well for us," asserts Dr. Ducker. "We devel- oped these genetic knockouts for different metabolic enzymes, which then can be used to develop a metabolomic fingerprint. Next, we can screen compounds and match the me- tabolomic fingerprint from the genetic knock- out to the desired metabolomic fingerprint induced by the compounds tested, to develop hits based on metabolomic differences." Taking Amino Acids off the Menu Another first-in-class cancer therapy tar- gets amino acid synthesis in cancer cells. "In addition to a higher metabolism of glucose by cancer cells (the Warburg effect), cancer tumors also use amino acids as a nutrient source," states Francesco Parlati, Ph.D., vice president of research at Calithera Bioscienc- es. Dr. Parlati and colleagues followed up on this observation by developing a small mol- ecule called CB-839. It is a compound that functions as a glutaminase inhibitor. Specifi- cally, it blocks the ability of tumors to use glutamine for metabolic needs. "We discovered CB-839 at Calithera while looking for compounds which target metab- olism," he recalls. "We knew that tumor cells also consume a lot of glutamine, the most abundant amino acids in the blood plasma of humans. Hence, targeting glutaminase in- hibitors made sense. After several rounds of perfecting the candidate via structure–activity relationship (SAR) studies, we saw good re- sults in triple-negative breast cancer cell lines and renal cell carcinoma cell lines." "CB-839 showed anticancer activity in several preclinical models," reports Dr. Par- lati. "Mechanistically, CB-839 reduces the levels of key intermediates in the tricarbox- ylic acid cycle, as well as levels of glutathione and nucleotides. Looking at potential combi- nations of cancer drugs, we rationalized that using a glutaminase inhibitor (CB-839) with an established drug that inhibits glucose me- tabolism, like everolimus, would improve the effectiveness of treatment." Imaging Metabolic Flux Another approach to drug development can be found in the imaging of tumors in patients. Magnetic resonance imaging (MRI) allows the visualization of tumor anatomy. However, the metabolism of tumors can also be assessed with a few modifications. "Normally, MRI depends on the spin of electrons in the protons of water," says John Kurhanewicz, Ph.D., professor of pharma- ceutical chemistry at the University of Cali- fornia, San Francisco. "This is not a prob- lem, as the human body is made up of lots of water. But to look at other molecules, we need to be able to go after different at- oms. The simplest way to do this, without getting into complicated physics, it to label compounds of interest with carbon-13 mol- ecules." Carbon-13 is a naturally occurring, non- radioactive isotope of carbon; it occurs in about 1% of all the carbon in nature, with 99% of the carbon in natural being car- bon-12. The take-home message is that or- ganic compounds labeled with carbon-13 can be detected on MRI imaging. "Unfortunately, the signal for a carbon-13 labeled compounds is very low," John Kurhanewicz points out. "To boost the sig- nal, we hyperpolarize the carbon-13 atoms in a glucose molecule immediately before trans- fusing the solution into patients. This hyper- polarization step boosts the signal intensity about 100,000 times that of nonhyperpolar- ized solutions." Applications of this technique to prostate cancers are especially interesting. The infor- mation about glucose metabolism of an ab- normal growth of the prostate gland is add- ed to other source of information, such as the anatomical findings from normal MRI, studies of blood supply and perfusion, and microstructure changes. This multiparamet- ric tool is very powerful diagnostically. In cases of prostate cancer, clinicians must answer a key question: How aggressive is the tumor? The answer will help the clinician de- velop a course of treatment. "Having recourse to an approach that ex- ploits carbon-13-labeled compounds, we can determine the pyruvate to lactate flux," as- serts Dr. Kurhanewicz. "This particular flux goes up much higher in high-grade prostate cancers. Hence, we have developed this as a biomarker for aggressive prostate cancer." Dr. Kurhanewicz believes that there is much room for growth by applying this technique to other cancers. The monitoring of hyperpolarized carbon-13 pyruvate-to- lactate flux is just one of the technique's po- tential applications. "We have also been able to look at pH and redox levels," Dr. Kurhanewicz elabo- rates. "We are interested in collaboratively moving forward to apply this approach to a variety of cancers. This sort of work could be used to aid in the diagnosis and treatment of cancer patients as well as stratifying patients for clinical trials and/or treatments." Innovations in technical fields continue to offer promising approaches to finding new treatments for cancer. Additionally, these first-in-class candidates further the under- standing of cancer metabolism, by proving where interference with metabolism inhibits the ability of cancer cells to proliferate and survive. Metabolic Quirks Continued from page 14 OMICS Insights Genomics & Proteomics The Oakland, California-based company Omica, a leading provider of clinical genome interpretation software and services, recently revealed its new name, logo, and brand identity, calling itself Fabric Genomics. Concomitantly, the or- ganization launched Fabric Enterprise TM , an optimized com- putational genomics platform enabling secondary analysis, rapid annotation, guideline-driven variant classification, and clinical reporting for both hereditary disease and oncology. "As a result of our recent acquisition, related capability expansions, and technology partnerships, it was time to rei- magine our company's broader role in the future of health- care," said Matt Tindall, CEO of Fabric Genomics. "Our role, along with our partners, is to secure, manage, analyze, inter- pret, and weave genetic data into the fabric of healthcare to drive behavior change, cost efficiency, and better outcomes. The idea that we can unlock genetic information, unlike any other company, to inform important healthcare decisions, gave rise to Fabric Genomics." In the midst of its new branding and platform launch, Fabric Genomics also announced a technology partnership with Sentieon, which develops highly optimized algorithms for bioinformatics applications. This new partnership, set to enhance Fabric Genomics' secondary analysis capabilities within Fabric Enterprise, spawning Fabric Standard TM , which is ten times faster than commonly adopted bioinformatic tools. Fabric Standard has no down-sampling of reads and is deterministic, even when running on multiple threads. This leads to more accurate scientific results and better overall efficiency. "By adding Sentieon's award-winning algorithms to Fabric Enterprise, we can deliver a seamless end-to-end solution for genomic data analysis," Tindall noted. "This marks a broad expansion in our capabilities as a company and provides our customers with the option to work with one software part- ner for all their NGS testing needs." Jun Ye, Ph.D., Sentieon's CEO added that "working with Fabric Genomics, Sentieon can help to improve patient care around the world with a total solution for clinical care. We an- ticipate opportunities to build important and powerful new applications with the Fabric Genomics team." n Omica Rebrands to Fabric Genomics, Signs Key Partnership with Sentieon Cancer cells utilize both glucose and glutamine for growth. At Calithera Biosciences, scientists have found that a cancer cell's ability to use glutamine for growth can be inhibited by using a potent, specific glutaminase inhibitor, CB-839. In combination with everolimus, CB-839 leads to a synergistic effect in decreasing tumor size.

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