1. Eastman, Peggy

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"Cancers: Can We Beat the Odds?" was the title of this year's scientific program at the annual meeting of the National Academy of Medicine (NAM), one of three components of the National Academy of Sciences in Washington, D.C.

National Academy of ... - Click to enlarge in new windowNational Academy of Medicine; cancer. National Academy of Medicine; cancer

"To my knowledge, this is the first time the scientific program has focused on cancer," stated Story C. Landis, PhD, program chair and Scientist Emeritus at the National Institute of Neurological Disorders and Stroke, one of the institutes of the NIH. "I find that surprising," said Landis, who noted that two out of five Americans will receive a cancer diagnosis during their lifetimes. She told Oncology Times that the challenge was selecting topics for the meeting because there were so many choices in the field.


The topic was chosen a year ago and the recent selection of James P. Allison, PhD, as a co-recipient of the Nobel Prize in Physiology or Medicine for his work on cancer immunotherapy turned out to be prescient. Allison is Chair of the Department of Immunology at the University of Texas MD Anderson Cancer Center.



"This is an amazing time for cancer," said keynote speaker Laurie H. Glimcher, MD, President and CEO of the Dana-Farber Cancer Institute, Director of the Dana Farber/Harvard Cancer Center, and Professor of Medicine at Harvard Medical School.


"It was known for years that T-cell infiltration into tumors correlates with prognosis," Glimcher noted. She said that back in the late 1800s William P. Coley, MD, sold "Coley's toxins" in bottles to boost immunity and fight cancer-a primitive approach that did not work.


Today, she explained that immunotherapy encompasses checkpoint inhibitors, adoptive T-cell therapy, cancer vaccines, and changing the immunosupressive tumor microenvironment-a field that is in its infancy. While checkpoint inhibitors are a major advance, Glimcher noted they are approved for just eight cancers, and only a minority of patients respond to them.


"What we're really looking for is combination immunotherapy without too much toxicity," she stated. Glimcher then described her preclinical research on the tumor microenvironment, specifically endoplasmic reticulum stress response-targeting immunotherapies. She and her colleagues have identified the IRE1/XBP1 cell signaling pathway as a therapeutic target because it robs T cells of their efficacy. IRB1 is an essential component of the unfolded protein response pathway, while the transcription factor XBP1 acts to regulate endothelial cell proliferation through growth factor pathways.


"If you think of the tumor as a castle, the microenvironment is a very hostile neighborhood," said Glimcher. "This is not Mister Rogers' neighborhood." She noted that, if activated, T cells cannot cross this hostile neighborhood, which she compared to the moat of a castle, and enter into the site of the tumor, then they cannot fight cancer cells effectively.


Glimcher said that in preclinical mouse models of ovarian cancer, the most lethal human gynecological cancer, proof-of-concept studies have shown that nanoparticles that silence the IRE1/XBP1 pathway boost an anti-tumor immune response. In addition, proof-of-concept studies have shown that IRE1/XBP1 deletion in dendritic cells impairs the growth of ovarian cancer cells in mouse models. Thus, she said, these studies demonstrate a "double whammy"-there is not only direct inhibition of tumor cells, but also restoration of the power of T cells to fight the cancerous tumor.


"We are talking about changing the metabolism of the T cell," said Glimcher. "If you silence IRE1/XBP1, you reverse the metabolic dysfunction of T cells." Asked by Oncology Times when this innovative approach might be tested in clinical trials of human subjects, she replied, "Who knows?" She noted that many biotechnology companies fail. But in her keynote talk she said that studies on the tumor microenvironment are now attracting more scientific attention, and after decades of her own basic research she is hopeful.


Combination Treatments

The need for evidence-based combinations in cancer treatment cited by Glimcher was a recurring theme at the NAM meeting. "We can't get away with single-drug therapy; we need rational combinations," said panelist Charles L. Sawyers, MD, an investigator at the Howard Hughes Medical Institute, Marie-Jose and Harvey Kravis Chair in Human Oncology & Pathogenesis, and Chairman of the Human Oncology & Pathogenesis Program at Memorial Sloan Kettering Cancer Center.


Sawyers has been honored for his work on the ABL kinase inhibitor imatinib for patients with chronic myeloid leukemia (CML) and on the second-generation ABL inhibitor dasatinib to overcome imatinib resistance. He said that as far back as 2001 patients on imatinib were beginning to relapse, highlighting the fact that monotherapy is rarely sufficient. Sawyers said that while concerns about toxicities with combination therapy are real, these are generally manageable. "I actually think we're a little too scared of toxicity" with combinations, he noted.


Agreeing on the need for rational therapeutic combinations in cancer treatment was panelist Kornelia Polyak, MD, PhD, Professor of Medicine at Dana-Farber Cancer Institute and Harvard Medical School. She noted that intra-tumor heterogeneity is prognostic; the more heterogeneity the more resistance to treatment. "Combinations are really the way to go to treat heterogeneous tumors," said Polyak. "I would like to see much more creative thinking about the use of combinations much earlier."


Introduction of Genomics

Panelists at the NAM meeting stressed the need for full integration of genomics into cancer diagnosis and treatment. About 17.5 percent of patients with advanced cancer have an actionable mutation, said Kenneth Offit, MD, MPH, Chief of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, where he holds the Niehaus Chair in Inherited Cancer Genomics. "The burden of hereditary cancer is larger than we thought, and depends on type, stage, and ancestry."


Offit emphasized that in an era of rapidly proliferating commercial genomic tests, it is essential for medical professionals to take responsibility for and control of genomic testing, diagnosis, and treatment. "We need the oncology community to embrace genetic counseling," he said. "If we don't step up to the plate, we leave it to the for-profit sector."


Offit told Oncology Times, "We're doing a reasonable job of it." While genomic testing can add increased burdens to a busy clinical practice, "there's a huge amount of interest in genomics," and he praised ASCO for taking the lead in providing professional education and resources on genomics.


Advances in genomics have changed diagnosis in oncology and made treatments much more precise, but there are barriers to its full integration into practice, said panelist Elaine R. Mardis, PhD, Nationwide Foundation Chair of Genomic Medicine, Co-Executive Director of the Institute for Genomic Medicine at Nationwide Children's Hospital, and Professor of Pediatrics at The Ohio State University College of Medicine.


She cited the fact that not all patients have access to genomic testing; drugs target only about 20 percent of cancer genes; not all targeted drugs are equivalent with respect to efficacy; there are still gaps in understanding mutations, especially which ones drive the cancerous process; and, as Sawyers noted, most patients treated with monotherapy-even when it is targeted-develop resistance.


In addition, Mardis said that oncologists' level of comfort with genomic testing is not really there if they have been in practice for a relatively long time. She also noted that the analysis of genomic data "is not always straightforward," and there is a need for tools to help interpret these data. She suggested that what oncologists are really looking for is a demonstrated clinical benefit of genomic testing for their patients.


Cancer Prevention

In a session on cancer prevention at the NAM meeting, panelists discussed ways of using available scientific knowledge to lower risk. "We could reduce cancer deaths by 60 percent by paying attention to known risk factors," said session moderator Otis W. Brawley, MD, MACP, FASCO, FACE, Chief Medical Officer of the American Cancer Society and Professor of Hematology, Medical Oncology, Medicine and Epidemiology at Emory University. Brawley decried the U.S. disparities in cancer access and care that account for about one in four cancer deaths.


Agreeing with Brawley on the need to reduce known risk factors was panelist Douglas R. Lowy, MD, Deputy Director of the NCI. Lowy, who has been honored for his research leading to the HPV vaccine, said uptake of this preventive vaccine still lags. "Increased vaccine uptake in the United States is needed to achieve personal protection for more individuals and greater herd immunity."


What is needed now is "precision prevention" based on cancer risk, said panelist Ernest Hawk, MD, MPH, Vice President and Head, Division of Cancer Prevention and Population Sciences, and holder of the T. Boone Pickens Distinguished Chair for Early Prevention of Cancer at the University of Texas MD Anderson Cancer Center. Hawk said cancer risk can be assessed in patients by germline predisposition, dramatic exposures to cancer-causing substances, and subclinical neoplasia. Then precision prevention can be used to reduce risk. For example, he said, in patients with Lynch syndrome, colonoscopy at 3-year intervals and aspirin use can markedly reduce the incidence of colorectal cancer.


Hawk said the Affordable Care Act, which expanded coverage for disease prevention, "has been a very important step forward in prevention across the country." He also added, "I think the potential for chemoprevention is profound," especially in high-risk people. But he noted that chemoprevention has needed to overcome the chilling effect of the Carotene and Retinol Efficacy Trial (CARET), which was halted early in January 1996. CARET showed no benefit and a substantial harmful effect of taking beta carotene and retinol in more than 18,000 people at high risk for lung cancer.


Obesity as a known risk factor for many cancers was discussed by panelist Cornelia Ulrich, MS, PhD, Senior Director of the Comprehensive Cancer Center at the Huntsman Cancer Institute and a Jon M. and Karen Huntsman Presidential Professor in Cancer Research in the Department of Population Sciences at the University of Utah. "Adipose tissue is emerging as a key player in cancer development," she noted, and those effects go beyond just fat storage. "Obesity is still on the rise."


She advocated a national effort to reduce consumption of sugar-sweetened drinks-which she said she knows is a politically charged topic-and praised the Transdisciplinary Research on Energetics and Cancer (TREC) centers on nutrition, energy balance, and physical activity established by the NCI in response to the U.S. obesity epidemic. TREC, administered by NCI's Division of Cancer Control and Population Sciences, is intended to complement efforts of the NIH Obesity Task Force to lower the U.S. obesity rate.


Peggy Eastman is a contributing writer.


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