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Drug combination study reveals new clues to treatment resistance in deadly melanoma

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Drug combination study reveals new clues to treatment resistance in deadly melanoma

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Uveal melanoma is a rare, aggressive cancer that starts inside the eye and often spreads to the liver. Few treatment options exist, and unlike some forms of skin melanoma that can respond well to modern therapies, metastatic uveal melanoma (MUM) remains difficult to treat.

Now, a team of Thomas Jefferson University researchers has tested a potential drug combination for MUM in a clinical trial that uncovered clues about why some tumors are resistant to treatment.

The study, published in the journal Cancers, tested two drugs, defactinib and avutometinib, in 12 people with MUM. A novel technology called "synthetic lethality analysis" indicated that this combination should work to block two different pathways and suppress the growth of MUM cancer cells.

Unfortunately, the treatment did not produce the tumor shrinkage the researchers expected. After two treatment cycles, six patients had stable disease, meaning their tumors did not grow, while six patients' disease worsened.

"We were hoping that this was going to be a miracle combination," says oncologist and senior author of the study Takami Sato, M.D., Ph.D.

Although it was not what they had hoped for, the researchers saw an opportunity to learn from the unexpected results. They compared tumor samples taken before and after treatment and looked for differences between tumors that remained stable and those that continued to grow.

They saw that levels of an enzyme called ALDH1A3 increased after treatment in several patients whose disease progressed, while patients whose disease remained stable tended to have lower levels.


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