Investigation into the biology of small-cell lung cancer, or SCLC, has revealed a potential target for therapies tailored to this disease, according to a new study published today in Genes & Development. A team led by Dr. David MacPherson of Fred Hutchinson Cancer Research Center and Dr. Kwon-Sik Park at the University of Virginia identified a gene that promotes tumor development by supercharging the machinery that cells use to churn out proteins. In preclinical models of SCLC, a drug inhibitor of the protein-production process slowed the progression of small-cell lung tumors.
SCLC is an aggressive type of lung cancer that initially responds well to chemotherapy but almost always recurs. “Small-cell lung cancer patients are being treated with therapies that haven’t changed for 30 years,” MacPherson said. “In order to develop a biology-based treatment, we need to better understand the vulnerabilities of small-cell lung cancer.”
MacPherson, an assistant member of the Human Biology and Public Health Sciences divisions at Fred Hutch, is an expert in developing preclinical models that can help shed light on the biology of tumor development, progression and relapse. For his research he turned to characteristic genetic mutations in SCLC, which can provide clues to tumor biology. Genes in the Myc family, especially L-Myc, are often amplified in SCLC, which implies they may influence cancer development or recurrence. The team’s findings suggest that treatments that target a specific pathway regulated by L-Myc could augment current therapies.
“We’ve showed that L-Myc is important in SCLC cells, and not just when it’s amplified,” he noted. “Basal levels of L-Myc are important in the biology of SCLC and could be therapeutically targetable.”
They found that forcing SCLC precursor cells to produce L-Myc (or other Myc family members) at high levels caused them to take on characteristics of tumor cells. In two different preclinical models of SCLC development, the team saw that removing the gene encoding L-Myc dramatically reduced the number of small-cell lung tumors.
MacPherson, Park and colleagues showed that L-Myc promotes tumor development by turning on genes that regulate pathways involved in protein synthesis. Upping L-Myc levels, in turn, led to increased protein production. A drug to target protein-production pathways, called CX-5461, is already in clinical testing for blood cancers. When the researchers used this drug to suppress protein-production pathways in a preclinical model of SCLC, they found that it either prompted tumor regression or prevented progression of disease.
“Now we need to look more deeply at the potential of inhibiting [protein synthesis] in SCLC patients,” MacPherson said. His team’s findings suggest that even normal levels of L-Myc play a role in SCLC development, and other research suggests that extra copies of the gene may be critical to the biology of SCLC relapse after treatment.
MacPherson and colleagues plan to continue testing the efficacy of CX-5461 in various preclinical models to see whether this drug may be combined with current therapies to prevent relapse after initial treatment response or target relapsed disease. In collaboration with clinicians at Seattle Cancer Care Alliance, the team has developed models using patient samples in which they will measure the efficacy of CX-5461 against SCLC.
Sabrina Richards / Fred Hutch News Service
Fred Hutch virologist Dr. Trevor Bedford is among 22 newly named Pew scholars in the biomedical sciences, a prestigious program that rewards exceptional early-career scientists with four years of funding to pursue innovative research. Bedford plans to use the $240,000 award for his work on nextstrain.org, a prototype software program that analyzes and tracks genetic mutations during disease outbreaks and displays the results in real time to guide public health interventions.
In fact, when the award was announced today, Bedford was in Brazil traveling by chartered bus with the ZiBRA project to do real-time sequencing of the Zika virus genome.
“Prioritizing samples, wrangling metadata, building database,” he tweeted. "Team working ridiculously hard. Processing >100 RT samples per day."
Analyzing and illustrating patterns of epidemic growth, spread and evolution in real time and predictively is a feat made possible by the increasing availability of genomic data and the willingness of researchers to share that data. The Pew award supports that kind of collaboration. It provides researchers with a lifetime community of scholars from diverse fields in biomedicine.
“Today, funding for basic research is more important than ever,” said Dr. Craig C. Mello, a 1995 Pew scholar and 2006 Nobel laureate who chairs the scholars program for The Pew Charitable Trusts, in a statement announcing the 2016 class. “But early-career scientists require support in other ways too. The Pew biomedical programs provide scholars with a wealth of practical advice and encouragement from other scientists — which we all need to be successful.”
Other 2016 Pew scholars in the biomedical sciences included researchers in neuroscience, bioengineering, cancer biology and immunology from Harvard University, Stanford University, Scripps Research Institute and the University of Pennsylvania, among other institutions.
— Mary Engel / Fred Hutch News Service
Drs. Denise Galloway and Garnet Anderson, two researchers that have made an enormous impact on cancer prevention, have each been named recipients of Fred Hutch 40th Anniversary Endowed Chairs.
The honorary positions, which include financial support for their continuing research, were created at the request of Fred Hutchinson Cancer Research Center President and Director Dr. Gary Gilliland, who has set a goal of increasing the number of endowed faculty chairs as an additional way to reward and retain top talent. Funding for the two endowed chairs was provided by private donors, who pledged their support during the December 2015 Hutch Holiday Gala, the cancer center’s largest annual fundraising event, which also celebrated the 40th anniversary of the founding of the research center.
Both researchers made their mark in cancer prevention research following very different paths. Galloway is a virologist and associate director of Fred Hutch’s Human Biology division. Her early work on cancer-promoting viruses led to the development of the human papillomavirus vaccine. It stymies a variety of HPV viruses responsible for cervical cancer, anal cancers and a type of head and neck tumor.
She continues her efforts to understand HPV and make the vaccine even better. She and her colleagues are studying B cells, the blood cells stimulated by vaccines to make protective antibodies, to learn how the “memories” of these immune cells are created. They are experimenting to find out if a two-dose HPV vaccine ― or even a single dose ― will be just as effective as the current three. “Reducing the number of doses will not only reduce the cost but hopefully will result in broader coverage among the population,’’ Galloway said.
Anderson is a biostatistician and senior vice president and director of Fred Hutch’s Public Health Sciences Division, which is renowned for studies that generate information on ways to reduce the risk of cancer and other dangerous chronic illnesses, particularly those that affect women. Early in her career at Fred Hutch, she assumed a central role in the massive National Institutes of Health-sponsored Women’s Health Initiative, which aimed to reduce heart disease as well as breast and colorectal cancers among women. In 2002, the WHI showed the significant health risks of combined hormone replacement therapy, which at the time was prescribed to millions of postmenopausal women in the United States. Those findings triggered a 50 percent decline in the use of HRT. Ten years later in the U.S. alone, there were an estimated 126,000 fewer breast cancer cases, 76,000 fewer cases of cardiovascular disease and 80,000 fewer cases of potentially deadly blood clots.
Today, as principal investigator of the WHI Clinical Coordinating Center, housed at Fred Hutch, she is leading an effort to gather tumor samples and data of study participants, many of whom are now in their 90s. The study will examine how tumor subtypes and their treatments are associated with health, quality of life and survival in older women. When told she had been named to a 40th Anniversary Endowed Chair, Anderson recalled she was almost speechless. “It really makes me feel like the institution is behind me,” she said. “They always have been, but this is a tangible, very gratifying and visible acknowledgement of that support.”
Sabin Russell / Fred Hutch News Service