1114 | CANCER DISCOVERY NOVEMBER 2015 www.aacrjournals.org

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Precision Medicine for Pediatric cancer

In likely the first study of its kind in children, researchers used genomic sequencing data from patients’ advanced and rare cancers to suggest effective treatment options. The findings dem-onstrate the feasibility of incorporating genomic information into the clinical management of pediatric patients.

In the single-site, observational study, 91 children and young adults with relapsed, refractory, or rare cancers underwent whole-exome and transcriptome sequencing. The data were then interpreted and analyzed by a tumor board made up of oncolo-gists, geneticists, and other experts. Actionable findings were reported for 42 of the patients—including 15 of 28 patients with hematologic malignan-cies and 27 of 63 with solid tumors. Based on the data, physicians changed the treatment for 14 patients, nine of whom went into partial or complete remission (JAMA 2015;314:913–25).

“This is one of the first comprehen-sive DNA/RNA sequencing platforms implemented in pediatric patients with advanced cancer,” says the study’s senior author, Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology at the University of Michigan in Ann Arbor. “We showed that it is possible to carry this out in a regimented fashion and to impact the individual management of patients in terms of the potential clini-cal use of targeted therapeutic agents.”

Investigators defined actionable findings as somatic mutations targeta-ble with an alternative therapy; molec-ular aberrations leading to changes in a patient’s diagnosis; or cancer-related germline mutations that could inform genetic counseling.

However, many patients with actionable findings experienced tumor progression before the results could be acted upon, partly due to the time it took to convene the tumor board and interpret the findings. The median time from biopsy to sequencing analy-sis and treatment recommendations was more than 6 weeks.

Access to targeted therapies was another limiting factor, says Chinnaiyan.

In some cases, patients with potentially actionable mutations could not access treatment due to exclusion criteria for a clinical trial or lack of pediatric dosing information for a drug approved for adults.

“The pediatric oncology community will need to completely rethink models of drug development in the genomic era as rare diseases become even more rare based on genetically defined subsets,” notes an accompanying editorial (JAMA 2015;314:881–3). “Academic, federal, and industry leaders must overcome the current risk-aversion mentality that interferes with translational innovation and develop new mechanisms to more deftly develop and deliver drugs to children with cancer.”

The study has several limitations, the authors acknowledged, including lack of a control group to distinguish whether treatment changes based on the study actually improved outcomes compared with standard of care. In addition, because some tumors were sequenced from archival material, any new mutations that emerged during treatment would have been missed.

Although this study focused on patients with advanced cancer, the goal is to incorporate clinical sequencing earlier in the disease process, says Chinnaiyan.

“It’s exceedingly difficult to treat patients who have gone through many different therapeutic regimens because the tumor has developed so many resistance mechanisms,” he says. “Clinical sequencing efforts have the potential to improve clinical manage-ment if we can bring them in earlier in the course of cancer development.” n

researchers win coveted lasker awards

Three renowned scientists who made discoveries that advanced under-standing of genetics and biology—and that led to the development of new cancer therapies—have been honored for their work with prestigious prizes from the Albert and Mary Lasker Foundation. Among the most coveted honors in medicine, the awards each carry an honorarium of $250,000.

Evelyn M. Witkin, PhD, professor emerita at Rutgers, The State University

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robert D. schreiber, PhD, and Philip D. Greenberg, MD, have been named editors-in-chief of Cancer Immunology Re search, a peer-reviewed jour-nal launched in 2013 by the American Asso-ciation for Cancer Research. The journal publishes original articles reporting advances in cancer immunology and immunotherapies, from basic investiga-

tions to early translational studies and late-stage clinical trials. Schreiber and Greenberg succeed Glenn Dranoff, MD.

Schreiber is a professor of pathology and immunology and director of the Center for Human Immunology and Immunotherapy Programs at Washington University School of Medicine in St. Louis, MO. He and his colleagues have identified somatic mutations in tumors that give rise to tumor-specific mutant antigens.

Greenberg is a professor of medicine/oncology and immunology at the University of Washington and head of the Program in Immunology at the Fred Hutchinson Cancer Research Center in Seattle. He has stud-ied the principles underlying a T cell’s abil-ity to recognize and eliminate tumor cells, distinguish cancer cells from normal ones, and maintain their function in the tumor microenvironment.

The European Society for Medical Oncology (ESMO) bestowed its ESMO Award upon nathan cherny, MBBs, at the European Cancer Congress in Vienna,

Austria, at the end of September. The award recognizes the key role he has played in integrating palliative care into the practice of oncology, such as develop-ing training programs for oncologists and setting minimum standards for palliative care in cancer centers. Cherny is the director of the Cancer Pain and Palliative Care Service at Shaare Zedek Medical Center in Jerusalem, Israel.

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Robert D. Schreiber

Philip D. Greenberg

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NOVEMBER 2015 CANCER DISCOVERY | 1115

he says. “Consequently, the high affinity PD-1 protein penetrates deeper into tumors and, unlike antibodies, does not cause unwanted depletion of PD-L1–positive T cells that mediate antitumor immunity.”

Ring and his colleagues used directed evolution to design the small protein. Using this technique, they first created a library of over 100,000,000 different PD-1 variants that they displayed on the surface of yeast. They then used magnetic and fluorescence cell sorting techniques to select for the tightest binders to recombinant PD-L1 protein. Through increasingly more difficult binding conditions, they zeroed in on one variant that bound to PD-L1 about 50,000 times more tightly than wild-type PD-1.

To assess its effectiveness in pen-etrating solid tumors compared with anti–PD-L1 antibodies, the researchers labeled both proteins with fluorescent dyes and simultaneously injected them into mice. Using fluorescence micro-scopy, they visualized the degree of tumor penetration.

“We were able to directly see how well anti–PD-L1 antibodies and our high-affinity PD-1 protein penetrate tumors, and there was a striking dif-ference,” says Ring. “The antibody is mostly found close to blood vessels and at the tumor periphery, whereas the smaller PD-1 protein spreads more extensively throughout the tumor.”

They also found that the small protein was more effective at treating larger tumors than PD-L1 antibodies. Both therapies shrank tumors 50 mm3 in size, but only the small protein was effective against tumors measuring 150 mm3. Adding an anti-CTLA4 antibody to anti–PD-L1 therapy in the larger tumors did not improve the efficacy of anti–PD-L1, whereas combining an anti-CTLA4 antibody with the small protein resulted in greater efficacy compared with either treatment alone.

“Our hypothesis is that as tumors grow larger, the need for effective penetration by the therapeutic agent becomes more important,” says Ring.

Several issues should be addressed before the high-affinity protein is ready for clinical testing, the research-ers emphasize. For example, due to its small size, it is excreted from the body more quickly than antibodies, and

of New Jersey in New Brunswick, and Stephen J. Elledge, PhD, a professor of genetics at Brigham and Women’s Hos-pital in Boston, MA, shared the 2015 Albert Lasker Basic Medical Research Award for their studies illuminating the fundamentals of the DNA-damage response. James P. Allison, PhD, chair of Immunology at The University of Texas MD Anderson Cancer Center in Hou-ston, received the 2015 Lasker-DeBakey Clinical Medical Research Award for the discovery and development of a mono-clonal antibody therapy that releases the brakes on the immune system so that it can combat cancer.

Witkin began her work in 1944, studying the basis for radiation resist-ance. X-rays and ultraviolet light were known to cause inherited mutations, but the question of how remained a mystery. Working with bacteria, she exposed 50,000 cells to a very high dose of UV light, killing all but four. Those cells, Witkin discovered, overcame sensitivity to radiation by initiating what is now known as the DNA-damage response, which detects anomalies in DNA as well as genetic processes, such as DNA copying dur-ing cell division, that have gone awry. Alerted to the problems, cells trig-ger protective mechanisms to make repairs and ensure their survival.

Working with yeast four decades later, Elledge began to build on Wit-kin’s work by elucidating a signaling system that spurred multiple genes to produce proteins that contribute to DNA repair. He went on to detail the molecular pathway by which cells in more complex organisms, including humans, detect and fix damaged DNA, an essential ability for the prevention of cancer.

Rather than prevent cancer, Alli-son wanted to attack cancer that had already been diagnosed. He showed that the protein CTLA-4 limited T-cell activation, reining in the immune sys-tem. By suppressing CTLA-4, he found that disease-fighting T cells could be unleashed and destroy malignant cells. That discovery led to the development and approval of the CTLA-4–inhibiting drug ipilimumab (Yervoy; Bristol-Myers Squibb), a treatment that has pro-longed the lives of countless patients with metastatic melanoma. Researchers are now studying the drug as a treat-

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James Allison (left), Evelyn Witkin, and Stephen Elledge show off the Lasker Awards that they received in recognition of their groundbreaking work in immunology and genetics, respectively.

ment for other malignancies, including lung cancer and renal cell carcinoma.

The Lasker winners “have opened up new frontiers,” said Lasker Founda-tion President Claire Pomeroy, who bestowed the awards during a ceremony in New York, NY, on September 18. “They remind us all that investing in biological sciences and medical research is crucial for our future.”

Established in 1942, the Lasker Foun-dation strives to improve health by advo-cating for support of medical research. For 70 years, its eponymous awards have recognized “the contributions of scien-tists, clinicians and public servants who have made major advances in the under-standing, diagnosis, treatment, cure, or prevention of human disease.” n

high-affinity PD-1 Protein has Potential

A small, engineered protein that selectively binds to PD-L1 was more effective in shrinking tumors and syn-ergizing with other immunotherapies than conventional PD-L1 antibodies in a preclinical study, according to data presented at the CRI-CIMT-EATI-AACR International Cancer Immuno-therapy Conference in New York, NY, in September.

The high-affinity PD-1 protein may overcome some drawbacks of existing antibody-based immune checkpoint inhibitors, says study corresponding author Aaron Ring, an MD/PhD student at California’s Stanford Uni-versity School of Medicine who will soon join the faculty at Yale University School of Medicine in New Haven, CT.

“It is approximately 10 times smaller than an antibody and it lacks the anti-body ‘Fc’ moiety that is recognized by Fc receptors on cells like macrophages,”

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2015;5:1114-1115. Published OnlineFirst October 7, 2015.Cancer Discov     Researchers Win Coveted Lasker Awards

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Research. on January 18, 2021. © 2015 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Published OnlineFirst October 7, 2015; DOI: 10.1158/2159-8290.CD-NB2015-138