Anti-HIV drug halts disease progression in 25% of patients with fourth-line metastatic colorectal cancer
New clinical research shows that lamivudine, a reverse transcriptase inhibitor widely used in the treatment of HIV, halted disease progression in 25% of patients with fourth-line metastatic colorectal cancer. The results of the trial, published in Discovery of cancerraise the possibility of an unexpectedly promising direction in the treatment of cancer, and not just colorectal cancer.
The trial included 32 patients with advanced metastatic colon cancer whose disease progressed despite four lines of prior cancer treatments. The first nine patients received the standard dose of lamivudine approved for HIV. “After giving them just 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. After quadrupling the dosage, 23 other patients received treatment with lamivudine when it was highly tolerated.
The research team observed that 9 of the 32 patients, or 28%, had stable disease or a mixed response at the end of the trial. “This provides evidence that an HIV drug can be repurposed as a cancer treatment in patients with metastatic cancer,” Ting says. Although the research team did not observe any shrinkage of the tumor, the results are encouraging.
“If we see that kind of response with just one HIV drug, the obvious next trial is to see what else we can get with HAART, or highly active antiretroviral therapy,” Ting adds, referring to the regimen. three-drug standard for HIV treatment.
The first hints of this unusual drug trial have surfaced in Ting’s lab and those of his collaborators over the past decade. The team found that up to 50% of a tumor’s DNA was made up of ‘repetitive elements’, which were previously thought to be ‘junk DNA’. “Only the cancer cells produced these repeating elements, not the healthy cells,” Ting explains. Colorectal cancers produce copious amounts of repeating elements, as do cancers of the esophagus, lung, and many others. These repetitive elements spit out extraordinary levels of RNA that replicate in a virus-like life cycle by reverse transcription in what Ting describes at the repeatome level.
The repeatome acts much like a virus by relying on reverse transcription to replicate and move through the genome. “It’s a way for cancers to modify their genome to adapt to stress,” adds Ting, who came up with the idea to assess whether an HIV drug, lamivudine, could interfere with the process.
In their preclinical studies, Ting found that colorectal cancer cells were sensitive to lamivudine, which reduced their ability to move. The team also found that the drug induced DNA damage and interferon responses, an indication that the drug was triggering an inflammatory response in tumor cells. Although not proven or evaluated in this trial, Ting hypothesizes that the combination of reverse transcriptase inhibitor treatment and immunotherapy may encourage immune cells to become involved in these cancers.
Research shows that in a US population of HIV-positive patients receiving lifelong three-drug antiretroviral therapy, their incidence of colon, breast and prostate cancer was significantly lower than that of the general population. Ting thinks this type of therapy could prevent cancer or recurrence or turn overwhelming metastatic disease into a chronic disease like HIV.
We did the trial to see if we could learn anything new about cancer cell biology, and in doing so, we found this unexpected and very encouraging result. The stability of disease in such an advanced cancer patient population with a single agent is highly unusual and we hope to soon be able to initiate a larger phase III study with a three-drug reverse transcriptase inhibitor combination. »
David T. Ting, MD, Mass General Cancer Center
Massachusetts General Hospital
Rajurkar, M. et al. (2022) Reverse transcriptase inhibition disrupts the life cycle of repeat elements in colorectal cancer. Discovery of cancer. doi.org/10.1158/2159-8290.CD-21-1117.