Melanoma may be stoppable with drug that halts cancer cell proliferation

examining-a-mole

A drug already being tested in people as a treatment for cancer appears to show great promise in halting melanoma skin cancer. The drug – called pevonedistat – works in a way differently than intended and could also be effective against other cancers.
examining a mole
Melanoma is an aggressive skin cancer that develops when cells that give skin its color mutate and become cancerous. The researchers say they have found a drug that may stop the cancer progressing.
So says a new study from the University of Virginia School of Medicine in Charlottesville that was published in the journal EBioMedicine.

Lead researcher Tarek Abbas, assistant professor of radiation oncology, says:

“In fact, the drug is very effective on all melanomas, including those for which an effective therapeutic is lacking.”

Melanoma is an aggressive skin cancer that develops when melanocytes – the cells that give skin its color – mutate and become cancerous.

Around 80,000 Americans a year are diagnosed with melanoma, and around 10,000 die of it. As with many cancers, the chances of survival once the cancer has spread to other parts of the body (metastatis) are much reduced.

Pevonedistat is being investigated as a cancer treatment and is already being tested in people.

Drug works ‘downstream’ of intended target
Scientists are not sure exactly how pevonedistat works against cancer cells, except that it appears to shut down hundreds, and perhaps even thousands, of cell proteins.

Fast facts about melanoma
Melanoma accounts for only around 1 percent of skin cancers but is responsible for a large majority of skin cancer deaths
White people are 20 times more likely to develop melanoma than black people
Rates of melanoma have been rising for the last 30 years.
Learn more about melanoma
In the new study, Prof. Abbas and colleagues investigate the drug’s effect on a particular protein produced by a gene called CDT2.

The protein allows melanoma and other cancer cells to replicate with great speed – the feature that makes aggressive cancer so deadly.

Prof. Abbas says they believe the CDT2 protein is what allows the cancer cells to cope with the amount of replication they must undergo. He explains:

“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 researchers found that without the CDT2 protein, the malignant cancer cells stopped replicating and fell apart.

Prof. Abbas says the effect they have discovered is not what the drug was originally designed for – it is “way downstream” of the intended target.

Second-line therapy for resistant cancer
In their study, where they used human melanoma cell lines and also mice implanted with melanoma cells, the team found that pevonedistat stopped the progress of melanoma by influencing a molecular pathway involving the CDT2 protein called CRL4-CDT2-SET8/p21.

CDT2 is required for melanoma cell proliferation, and melanoma cells produce excessive amounts of CDT2 protein, as Prof. Abbas explains:

“These tumors, and not necessarily just melanoma, they are addicted to this gene. 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 CDT2 protein also occur in other types of tumor, such as in the brain and liver, note the researchers who suggest it may also serve as a prognostic marker.

We do not yet know how safe or effective pevonedistat is in humans, as tests are still under way. Prof. Abbas is hopeful, however, because of their findings, that it will be shown to be effective.

He and his colleagues showed that the drug appears to be effective in melanoma that resists current treatments – which is a major challenge in fighting this type of skin cancer.

If the drug passes the tests and the regulator approves it, then it could serve as a good second-line therapy for melanoma patients who do not respond to initial treatments, says Prof. Abbas.

“We have great hope that this drug will have very significant impact on melanoma in general.”

Prof. Tarek Abbas

Learn how a new app trains doctors to spot early stage skin cancer.

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