• HIV drug stabilizes disease progression

    From ScienceDaily@1:317/3 to All on Tue Apr 5 22:30:38 2022
    HIV drug stabilizes disease progression in metastatic colorectal cancer
    Using reverse transcriptase inhibitors raises the possibility of a new therapeutic strategy in cancer.

    Date:
    April 5, 2022
    Source:
    Massachusetts General Hospital
    Summary:
    Many cancers exhibit high levels of the reverse transcriptase
    enzyme.

    Single-agent lamivudine, a reverse transcriptase inhibitor, stopped
    disease progression in over 25% of patients with fourth-line
    refractory metastatic colorectal cancer. These results provide
    evidence for the evaluation of reverse transcriptase inhibitors
    as a new class of anti- cancer drugs.



    FULL STORY ==========================================================================
    New clinical research shows that lamivudine, a reverse transcriptase
    inhibitor widely used in HIV therapy, stopped disease progression in 25%
    of patients with fourth-line metastatic colorectal cancer. Findings
    from the trial, published in Cancer Discovery, raise the possibility
    of an unexpected promising direction in cancer treatment, not just
    colorectal cancer.


    ==========================================================================
    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 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. After adjusting the
    dosing four-fold, another 23 patients received lamivudine therapy where
    it was highly tolerated.

    The research team observed that 9 of the 32 patients, or 28%, had disease stability or mixed response at the end of the trial. "This provides
    evidence that an HIV drug can be repurposed as an anti-cancer therapy
    in metastatic cancer patients," says Ting. While the research team did
    not see tumor shrinkage, the results are encouraging.

    "If we see this kind of response with just one HIV drug, the next obvious
    trial is to see what else we can achieve with HAART, or highly active anti-retroviral therapy," adds Ting, referring to the standard three-drug regime for HIV treatment.

    The first clues to this unusual drug trial surfaced in Ting's lab and
    those of his collaborators over the past ten years. The team discovered
    that up to 50% of a tumor's DNA was composed of "repetitive elements,"
    which were previously considered "junk DNA." "Only cancer cells produced
    these repetitive element, not healthy cells," says Ting. 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.

    Research shows that in a U.S. population of HIV patients receiving
    three-drug anti-retroviral therapy for life, their incidence of colon,
    breast, and prostate cancer was significantly less than the general
    population. Ting speculates this kind of therapy might prevent a cancer
    or a recurrence or turn a crushing metastatic disease into a chronic
    disease like HIV.

    "We did the trial to see if we could learn something new about the
    biology of cancer cells and in the process found this unexpected, very encouraging result," says Ting. "Disease stability in a cancer patient population this advanced, with just one single agent, is highly unusual
    and we are hoping we can soon initiate a larger Phase III study with a three-drug reverse transcriptase inhibitor combination." This work was supported with grants from the National Institutes of Health, Gateway for Cancer Research, Stand Up To Cancer (SU2C), National Science Foundation, Burroughs Wellcome Fund, V Foundation for Cancer Research, Affymetrix,
    Inc., ACD-Biotechne, Robert L. Fine Cancer Research Foundation, and the Pershing Square Sohn Prize -- Mark Foundation Fellowship.


    ========================================================================== Story Source: Materials provided by Massachusetts_General_Hospital. Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Mihir Rajurkar, Aparna R. Parikh, Alexander Solovyov, Eunae You,
    Anupriya
    S. Kulkarni, Chong Chu, Katherine H. Xu, Christopher Jaicks,
    Martin S.

    Taylor, Connie Wu, Katherine A. Alexander, Charly R. Good, Annamaria
    Szabolcs, Stefanie Gerstberger, Antuan V. Tran, Nova Xu, Richard Y.

    Ebright, Emily E. Van Seventer, Kevin D. Vo, Eric C. Tai, Chenyue
    Lu, Jasmin Joseph-Chazan, Michael J. Raabe, Linda T. Nieman,
    Niyati Desai, Kshitij S. Arora, Matteo Ligorio, Vishal Thapar,
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    Garden, Yasmeen Senussi, Hui Zheng, Jill N. Allen, Lawrence S.

    Blaszkowsky, Jeffrey W. Clark, Lipika Goyal, Jennifer Y. Wo,
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    Ryan, Ryan B. Corcoran, Vikram Deshpande, Miguel N. Rivera,
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    Aryee, Theodore S. Hong, Shelley L. Berger, David R. Walt,
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    Burns, Peter J. Park, Benjamin D. Greenbaum, David T. Ting. Reverse
    Transcriptase Inhibition Disrupts Repeat Element Life
    Cycle in Colorectal Cancer. Cancer Discovery, 2022; DOI:
    10.1158/2159-8290.CD-21-1117 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220405102834.htm

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