The trial included 32 patients with advanced metastatic colon cancer whose disease progressed despite four lines of previous cancer treatments. The first nine patients received the standard HIV-approved dose of lamivudine. After adjusting the dosing four-fold, another 23 patients received lamivudine therapy where it was highly tolerated.
“After giving them only this one drug – nothing else – we saw signs of disease stability,” says co-senior author David T. Ting, MD, of the Mass General Cancer Center.
Nine of the 32 patients, or 28%, had disease stability or mixed response at the end of the trial. There was not tumor shrinkage but it shows promise that an HIV drug can be re-purposed as an anti-cancer therapy in metastatic cancer patients. And if one HIV drug can be promising, it makes sense that the next obvious trial is to see what else we can achieve with HAART, highly active anti-retroviral therapy, the standard three-drug regime for HIV treatment, can achieve.
The first clues that led to the drug trial were when the team discovered that up to 50 percent of a tumor’s DNA was composed of repetitive elements, “junk DNA”. but that only cancer cells produced these repetitive element, not healthy ones. Colorectal cancers produce abundant amounts of repetitive elements, as do cancers of the esophagus, lung, and several others. These repetitive elements spew out extraordinary levels of RNA which replicate in a viral-like life cycle through reverse transcription into what Ting describes at the repeatome.
The repeatome acts much like a virus does relying on reverse transcription to replicate itself and move in the genome. “It’s a way for cancers to change their genome to adapt to stress,” adds Ting, who had the idea to assess whether an HIV drug, lamivudine, might interfere with the process.
In their preclinical studies, Ting found that colorectal cancer cells were sensitive to lamivudine, reducing their ability to move. The team also discovered that the drug induced DNA damage and interferon responses, an indication that the drug triggered an inflammatory response in the tumor cells. Although not proven or evaluated in this trial, Ting theorizes that pairing reverse transcriptase inhibitor therapy with immunotherapy might encourage immune cells to become involved in these cancers.
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