NEWS IN BRIEF 1298 | CANCER DISCOVERYDECEMBER 2016 www.aacrjournals.org • Gilead Sciences’ entospletinib, an inhibitor of the tyrosine kinase Syk, which blocks B-cell receptor signaling Three to six more drugs may be added over the course of the trial, which will run for 3 to 5 years. “This is about working toward a common goal,” said Levine. “We really want to make a difference for our patients.” –Karen Weintraub ■ Nobel Prize Honors Autophagy Discovery Japanese cell biologist Yoshinori Ohsumi, PhD, has been awarded this year’s Nobel Prize in Physiology or Medicine for his discovery of autophagy. His groundbreaking studies in yeast illuminated how cells collect and break down intracellular proteins and organelles, a process that is critical to the survival of both normal cells and some cancerous ones. “His discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes, such as in the adaptation to starvation or response to infection,” noted the Nobel Committee in announcing the award in October. The concept of autophagy was first observed in the 1960s, but little was known about its underlying mecha- nisms until Ohsumi conducted a series of experiments with baker’s yeast in the early 1990s. Those studies eventually led him to identify the genes—and the proteins they encode—that control autophagy, and to show that a corre- sponding mechanism exists in humans. Autophagy is a self-defense mecha- nism that prevents the accumulation of garbage or potentially toxic material in cells, such as damaged proteins and organelles. In normal cells, it serves as a buffer during metabolic stress by recycling intracellular components. It also helps to eliminate invading bac- teria and viruses following infection, promote embryo development and cell differentiation, and counteract the negative consequences of aging. Ohsumi verified that the process exists in yeast cells by studying how autophagy delivers cargo for degra- dation in the vacuole. (In human cells, similarly, autophagosomes fuse with lysosomes, which contain enzymes that degrade proteins and organelles.) He then cultivated cells that lacked vacuolar degradation enzymes, starved them, and was able to observe the vacuoles fill with small vesicles holding proteins to be degraded—known as autophagosomes. In another set of experiments, Ohsumi exposed engineered yeast cells to a chem- ical that randomly introduced mutations in many genes, then induced autophagy. As a result, he identified many different proteins and protein complexes that regulate distinct stages of autophago- some initiation and formation. “Ohsumi used yeast as a model system to identify the mechanisms it uses to survive nitrogen starvation and the genes essential for the autophagy pathway,” says Eileen White, PhD, professor of molecular biology and biochemistry at Rutgers University and deputy director and associate director for Basic Science at Rutgers Cancer Institute of New Jersey, in New Brunswick. “By doing this, he opened up a whole new field of investigation.” Recent research has revealed that some cancer cells in hypoxic regions also use autophagy to survive metabolic stress, suggesting that the process may be a via- ble drug target, says White. Companies are now working on autophagy inhibi- tors, possibly to augment the activity of targeted drugs. Multiple clinical trials are testing hydroxychloroquine (HCQ), an antimalarial drug that interferes with lysosome function, in combination cancer therapy. For example, a phase II trial is assessing HCQ combined with the BRAF inhibitor dabrafenib (Tafinlar; Novartis) and trametinib, a MEK inhibi- tor (Mekinist; Novartis), in patients with advanced BRAF-mutant melanoma. “The discovery of autophagy genes and how they enable lysosomal deg- radation and recycling of organelles and proteins has provided a critical platform for understanding how autophagy plays a role in resistance to cancer therapy,” says Ravi Amaravadi, MD, a medical oncologist at the Uni- versity of Pennsylvania in Philadelphia, who led a series of early-phase clinical trials testing HCQ in combination with targeted therapies. “Ohsumi’s work provided the framework to pro- pose biomarkers and targets for drug discovery that could improve the efficacy of cancer therapies in a number of cancers.” –Janet Colwell ■ announcing the trial. With LLS acting as a neutral party, more pharmaceuti- cal companies may join the effort to bring drugs to market more quickly. “The secret sauce of this trial is the idea that we’re going to work faster by collaborating in open and transparent ways,” said Ross Levine, MD, of Mem- orial Sloan Kettering Cancer Center (MSKCC) in New York, NY. In addition to MSKCC, the Ohio State University Comprehensive Cancer Center (OSUCCC) in Columbus, Oregon Health & Science University Knight Cancer Institute in Portland, and Dana-Farber Cancer Institute and Massachusetts General Hospital, both in Boston, will serve as the initial trial sites. Researchers plan to enroll 500 patients over age 60 newly diagnosed with AML in the trial. Participants will have their cancer’s genome sequenced and be put into a trial arm based on nine different genomic signatures, said John Byrd, MD, of OSUCCC. Unlike other trials, none of the participants will receive standard chemotherapy alone. If there is not a suitable drug match for a patient’s genetic markers, they will be offered chemotherapy in combination with an existing targeted therapy, Byrd explained. Patients who do not res- pond to their investigational drug can also receive conventional therapy with the targeted therapy, he added. Most of the patients who will be eligible for the trial are unable to tol- erate intensive chemotherapy, so their outcomes are even worse than average, said Brian Druker, MD, director of the Knight Cancer Institute. The targeted therapies are expected to be better tolerated than toxic chemotherapy, and will be given after diagnosis, when they will likely be more effective, instead of waiting for disease relapse, he added. DeGennaro said that the trial will begin by testing these four drugs: • Alexion’s samalizumab (ALXN6000), a humanized monoclonal antibody that targets CD200 • Boehringer Ingelheim’s BI 836858, which induces antibody-dependent cellular cytotoxicity against CD33- expressing tumor cells • Celgene and Agios’s enasidenib (AG- 221/ CC-90007), a selective IDH2 inhibitor on July 26, 2020. © 2016 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst October 17, 2016; DOI: 10.1158/2159-8290.CD-NB2016-127