May even work on melanomas that have resisted treatment
An experimental cancer drug works differently than intended and shows significant promise for stopping melanoma and possibly other forms of cancer, research from the University of Virginia School of Medicine suggests. The findings also indicate the drug may be effective against melanomas that have resisted other forms of treatment.
The drug, pevonedistat, is already being tested in people. Scientists have been uncertain exactly how it kills cancer cells, as it shuts down many different cellular proteins – hundreds if not thousands. But the UVA researchers, led by Tarek Abbas, PhD, of the Department of Radiation Oncology and the UVA Cancer Center, have determined that the drug acts upon a particular protein that melanomas and other cancers rely on to replicate with great speed and deadly effect. By denying the cancers this essential ingredient, doctors may be able to stop melanomas and other forms of the disease.
“We think that this is what lets the cancer cells cope with the amount of replication they must undergo,” Abbas said. “They divide in uncontrolled fashion, and those cells that divide faster and more frequently are under tremendous replication stress, so these cancer cells needed to be able to develop a way to cope with that.”
The critical protein blocked by pevonedistat is produced by the gene CDT2, and it is vital for malignant cancer cells to survive. Without it, the cells stop replicating and begin to fall apart. “We have great understanding now for how the drug works,” Abbas said. “And we think the drug works not because of its intended target, but rather because it works on [the CDT2 protein] way downstream of that.”
Excessive amounts of the protein are produced in melanoma cells, and patients with high levels of it are less likely to survive. “These tumors, and not necessarily just melanoma, they are addicted to this gene,” Abbas said. “And that makes them very susceptible to the drug. In fact, we showed, that melanoma cells that have higher levels of expression of CDT2 are much more susceptible to the drug.”
High levels of the CDT2 protein are also found in many other tumors, he noted, including brain, breast and liver tumors. Doctors may one day use the level of the protein as a way to gauge disease prognosis.
‘We Have Great Hope’
The safety and effectiveness of pevonedistat in people is still being tested, and it is not yet available as a treatment. But Abbas, who has not been involved in the drug’s testing, is optimistic based on his findings. “We have great hope that this drug will have very significant impact on melanoma in general. … In fact, the drug is very effective on all melanomas, including those for which an effective therapeutic is lacking,” he said. “We actually show this drug can work on melanoma that resisted treatment, which is a major challenge in melanoma therapy. … If approved by the FDA and it moves forward, this drug could potentially be a good second-line therapy for those patients that fail initial treatment.”
No cure available for exposure to potentially deadly ionizing radiation
- UVA researchers have identified compounds that could lead to the first antidote for potentially deadly radiation exposure
- Research was spurred by government concern about terror attacks and nuclear accidents
- For people exposed to sufficient ionizing radiation, doctors can only try to ease their suffering until death
- 2016 is the 30th anniversary of the Chernobyl nuclear accident and the fifth anniversary of the Fukushima nuclear accident
University of Virginia School of Medicine researchers have identified promising drugs that could lead to the first antidote for radiation exposure that might result from a dirty bomb terror attack or a nuclear accident such as Chernobyl.
A gene that scientific dogma insists is inactive in adults actually plays a vital role in preventing the underlying cause of most heart attacks and strokes, researchers at the University of Virginia School of Medicine have determined. The discovery opens a new avenue for battling those deadly conditions, and it raises the tantalizing prospect that doctors could use the gene to prevent or delay at least some of the effects of aging.
“Finding a way to augment the expression of this gene in adult cells may have profound implications for promoting health and possibly reversing some of the detrimental effects with aging,” said researcher Gary K. Owens, PhD, director of UVA’s Robert M. Berne Cardiovascular Research Center.
Unexpected Protective Effect
The gene, Oct4, plays a key role in the development of all living organisms, but scientists have, until now, thought it was permanently inactivated after embryonic development. Some controversial studies have suggested it might have another function later in life, but the UVA researchers are the first to provide conclusive evidence of that: Owens and his colleagues have determined the gene plays a critical protective role during the formation of atherosclerotic plaques inside blood vessels. The rupturing of these plaques is the underlying cause of many heart attacks and strokes.
The researchers found that Oct4 controls the movement of smooth muscle cells into protective fibrous “caps” inside the plaques – caps that make the plaques less likely to rupture. The researchers also have provided evidence that the gene promotes many changes in gene expression that are beneficial in stabilizing the plaques.
This is exciting, because studies suggest that it may be possible to develop drugs or other therapeutic agents that target the Oct4 pathway as a means to reduce the incidence of heart attacks or stroke. “Our findings have major implications regarding possible novel therapeutic approaches for promoting stabilization of atherosclerotic plaques,” said Olga A. Cherepanova, PhD, a senior research scientist in Owens’ lab.