From Ideas to Impact
Discoveries Made With Pelotonia Support
The promise of Pelotonia is revealed in part by the discoveries made by teams of OSUCCC – James researchers who receive support from the annual event. Here are four examples.
Stress Gene Has Role in Tumor Metastasis
With a Pelotonia Idea Grant as partial support, a team of OSUCCC – James researchers has linked a stress gene called ATF3 in immune cells to the spread of breast-cancer cells from a tumor to other parts of the body. The spread, or metastasis, of cancer cells is the leading cause of death in cancer patients.
The findings, published in the Journal of Clinical Investigation, suggest that ATF3 may be a crucial link between stress and cancer. Previous studies have shown that stress is a risk factor for cancer. This research suggests that cancer cells, by acting as stress signals, coax immune cells that have been recruited to a tumor to express ATF3.
Though it’s unclear how, ATF3 promotes the immune cells to act erratically and give cancer an escape route from the tumor site to other areas of the body.
“If your body does not help cancer cells, they cannot spread as far,” says senior author Tsonwin Hai, PhD, professor of Medicine and a member of the OSUCCC – James Molecular Biology and Cancer Genetics Program. “So the rest of the cells in the body help cancer cells move to distant sites. And one of the unifying themes is stress.”
Hai says this stress gene could one day serve as a target for drugs to combat metastasis.
Loss of a Critical Tumor-Suppressor Genre is Explained
OSUCCC – James researchers have discovered a mechanism responsible for the loss of a critical tumor-suppressor gene in rhabdomyosarcoma and other soft-tissue sarcomas. The findings could guide the development of more effective therapies for these rare cancers, which strike mainly children and often respond poorly to treatment.
The researchers discovered that the tumor-suppressor gene called A20 is silenced not by mutation, as in many other cancers, but because a second molecule is lost – a small molecule called microRNA-29. They also found that microRNA-29 normally protects A20 from destruction. When microRNA-29 is missing, A20 is degraded. Loss of A20, in turn, leads to a rise in levels of a protein called NF-κB and to tumor progression.
The findings were published in the journal Science Signaling.
“We know that NF-κB promotes tumor growth, but we don’t know why it is upregulated in many cancers,” says principal investigator Denis Guttridge, PhD, professor of Molecular Virology, Immunology and Medical Genetics. “Our study indicates that it involves a regulatory circuit between NF-κB, microRNA-29 and the A20 tumor-suppressor gene. It also identifies NF-κB as a therapeutic target in sarcoma, and A20 and microRNA-29 as potential biomarkers for sarcoma.”
Guttridge notes that the findings move research a step closer toward developing microRNA-29 therapy against NF-κB activation in cancers.
A New Prognostic Marker and Treatment Target for Acute Leukemia
A study supported in part by Pelotonia dollars identified microRNA-155 as an independent prognostic marker and treatment target in certain patients with (AML). The study focused on patients whose leukemia cells, when viewed under a microscope, have normal-looking chromosomes. This category of AML is called cytogenetically normal acute myeloid leukemia (CN-AML).
The study found that when microRNA-155 is present at abnormally high levels in CN-AML cells, patients are less likely to have a complete remission, and they experience a shorter disease-free period and shorter overall survival.
The researchers say that miR-155 would be relatively easy to measure at diagnosis, suggesting that it could be a good marker for identifying patients at greater risk of recurrence.
“Our findings indicate that miR-155 expression is a strong and independent prognostic marker in CN-AML, and they provide clinical validation of data from preclinical models that support a crucial role of miR-155 in leukemia,” says senior author Clara D. Bloomfield, MD, a Distinguished University Professor at Ohio State, where she also serves as cancer scholar and senior adviser to the OSUCCC – James.
The findings also suggest that miR-155 plays a role in CN-AML development and could be a target for an emerging class of drugs designed to inhibit microRNAs, says first author Guido Marcucci, MD, professor of Hematology, a leukemia specialist and associate director for translational research at the OSUCCC – James.
Seven-Gene Score Might Help Determine Best AML Treatment
Pelotonia funding also helped Bloomfield, Marcucci and collaborators develop a novel method that might help guide the treatment of CN-AML patients.
Currently, doctors use chromosome markers and gene mutations to determine AML treatment. This study, published in the Journal of Clinical Oncology, developed a score based on seven mutated genes. Along with gene mutations, this AML score includes another gene alteration that influences cancer development called DNA methylation. Healthy cells use DNA methylation to reduce or silence a gene’s activity. Abnormal DNA methylation can shut down important tumor-suppressor genes and promote cancer development.
“To date, disease classification and prognostication for AML patients have been based largely on chromosomal and genetic markers, and changes that affect gene expression have not been considered,” says Bloomfield, who also holds the William Greenville Pace III Endowed Chair in Cancer Research at Ohio State.
“Here we show that DNA methylation in previously recognized and prognostically important mutated genes can identify novel patient subgroups, which might better help guide therapy,” she says.
Most adults with AML are not cured by current therapies. Only about 40 percent of patients younger than age 60, and about 10 percent of patients 60 and older, are alive after three years, so new strategies for treating the disease and for matching patients with the most promising treatment are needed, Bloomfield says.
The researchers computed the seven-gene score based on the number of genes in the panel that were highly expressed in patients’ AML cells, and retrospectively tested the score in two groups of older patients (age 60 and up) and two groups of younger patients (age 59 and under).
“For this seven-gene panel, the fewer highly expressed genes, the better the outcome,” says first author Marcucci. “In both younger and older patients, those who had no highly expressed genes, or had one highly expressed gene, had the best outcomes.”