Dr. Soheil Meshinchi, a pediatric oncologist and member of the Clinical Research Division at Fred Hutch, has received a $250,000, two-year Reach Grant from Alex’s Lemonade Stand Foundation, a nonprofit dedicated to finding cures for all kids with cancer. He will use the award for a study to identify drugs to target gene mutations unique to childhood acute myeloid leukemia.
The Reach Grant provides crucial funding at a critical point in the development of cancer therapy: preparation for Food and Drug Administration approval.
For the study, Meshinchi and colleagues will target pediatric-specific mutations on a gene called FLT3.
Acute myeloid leukemia, or AML, remains one of the most difficult challenges in pediatric oncology; more than half of children with the disease fail available therapies. Although FLT3 mutations may provide a therapeutic target, these mutations are not common in children.
“Through genomic sequencing we have discovered 32 different novel mutations in FLT3 gene that are unique to childhood AML and may provide the possibility of extending FLT3 inhibitors to a larger cohort of children with AML,” Meshinchi said. Before they can be used as a viable therapeutic target, the function of these novel mutations must be established and drugs must be identified that appropriately target them, he said.
The goal of the project is to use molecular cloning techniques developed in the Meshinchi Lab to engineer cells that express the mutant cells and determine if they can grow without external stimulation. In addition, as each type of mutation may have a different response to different drugs, mutant cells will be tested against a large number of FLT3 inhibitors as well as other targeted agents.
To optimize this analysis, Meshinchi and colleagues will utilize a robotic, high-throughput drug-screening platform that can rapidly test multiple cell lines against more than 160 drugs and generate a response profile that can be linked to mutation type. This approach will allow identification of precise mutations that would most benefit from the most appropriate drugs.
The data will be used in an upcoming clinical trial in which all patients with functional FLT3 mutations will be treated with the appropriate FLT3 inhibitor in order to improve their survival.
“For many children and their families facing a childhood cancer diagnosis and subsequent fight, the traditional treatment protocol will fail,” said Jay Scott, co-executive director of Alex’s Lemonade Stand Foundation. “Similarly to my daughter Alex’s battle, children and families will turn to clinical trials, whose outcomes can provide hope and the possibility of potential cures. We are dedicated to bringing promising research forward from the lab to the clinic.”
Based on an Alex’s Lemonade Stand Foundation news release.
When using genetic data to make treatment decisions for children with leukemia, it’s not if a particular cancer mutation is present that should drive treatment choices, it’s how common that mutation is in the cancer, argue the authors of a new study led out of Fred Hutchinson Cancer Research Center.
“The problem is when people say ‘mutation,’ they look at it as binary: yes/no,” said study leader Dr. Soheil Meshinchi, a member of Fred Hutch’s Clinical Research Division and a professor of pediatrics at the University of Washington. “So then they try to treat that [mutation], and they say ‘Well, [the treatment] doesn’t work; I don’t know why.’”
The new paper comes out of pilot phase of the largest-ever genetic sequencing effort in childhood acute myeloid leukemia, known as the TARGET AML Initiative. Treatment strategies for childhood AML have largely been based on data from adults; however, the genetic landscape of the disease is quite different in children. Currently, half of children with AML relapse even after intensive treatments. TARGET AML is designed to map out that landscape so that more effective treatment strategies can be developed for these young patients.
The recent study, published in the journal Cancer Research by a team of collaborators across the country, revealed a “laundry list” of mutations in samples from 20 children taken at diagnosis, remission, and relapse. But the most important part, Meshinchi said, was the data they gathered on a measure of how common a mutation is within a cancer, a measure called variant allele fraction.
The study revealed that the mutations with a high variant allele fraction at diagnosis – that is, those that were initially present in a greater proportion of a child’s cancer cells – were more likely to still be present at relapse, suggesting that these mutations are the most clinically significant.
“What’s in this paper is quite obvious, but unfortunately it’s an area that’s quite ignored when you’re talking about mutations in cancer,” Meshinchi said. “Sequencing is becoming so routine, that we’re now getting mutation data on most patients. So simply knowing the presence or absence of a mutation is not adequate for us to make clinical decisions. We need to know mutation burden.”
Susan Keown / Fred Hutch News Service
Documenting that it’s never too late to quit smoking, a large study co-led by Dr. Polly Newcomb, a member of the Public Health Sciences Division at Fred Hutch, has found that women who quit smoking after being diagnosed with breast cancer had a 33 percent lower risk of dying from their disease than those who continued to smoke.
"It's never too late to quit smoking, regardless of age, duration of smoking, or the time since breast cancer diagnosis," Newcomb said. "The benefits of cessation should be emphasized in the public health and clinical setting."
The study, co-authored by Dr. Michael Passarelli at the University of California, San Francsico, and coordinated by researchers at the University of Wisconsin School of Medicine and Public Health, involved more than 20,600 women with a history of breast cancer. It is one of the largest studies of survival outcomes according to smoking habits in women with a history of breast cancer. It is also the first study to assess smoking habits both before and after diagnosis.
The observational study, which followed participants on average a dozen years after diagnosis, compared the causes of death among four groups:
Participants were asked to report on such factors as whether they had smoked at least 100 cigarettes during their lifetime, their age when they started smoking, and the average number of cigarettes they smoked per day. The researchers controlled for several important risk factors that could impact survival, including alcohol consumption and body mass index.
The study, published in the Journal of Clinical Oncology, found that women who were active smokers a year prior to breast cancer diagnosis were more likely to die of breast cancer, respiratory cancer, other respiratory diseases or cardiovascular disease than women who had never smoked. The highest risks of death from breast cancer were observed among long-term smokers, women who smoked heavily or former smokers who quit fewer than five years before breast cancer diagnosis. In an accompanying editorial, the authors note that "smoking cessation may be as important as or more important than any other survivorship recommendation."
Approximately one in 10 cancer patients continued to smoke after their diagnosis and were more likely than those who had never smoked or had quit to die of breast cancer. Those who quit smoking after diagnosis had lower mortality from breast cancer and respiratory cancer.
The National Cancer Institute and Susan G. Komen for the Cure funded the study, which also involved investigators from Dartmouth Medical School, the H. Lee Moffitt Cancer Center and Research Institute, the University of North Carolina School of Medicine, the Harvard T.H. Chan School of Public Health and Brigham and Women’s Hospital.
Adapted from a UCSF news release