• Ovarian cancer: Potential therapeutic ta

    From ScienceDaily@1:317/3 to All on Thu Aug 5 21:30:42 2021
    Ovarian cancer: Potential therapeutic target identified

    Date:
    August 5, 2021
    Source:
    University of Alabama at Birmingham
    Summary:
    A gene called DOT1L appears to play a role in progression and
    severity of ovarian cancer, and inhibitors of the DOT1L enzyme
    may offer a new therapeutic approach for the disease, researchers
    say in a new study. The need is clear -- despite decades of work
    to develop new treatment modalities, the five-year survival of
    patients with advanced ovarian cancer is between 10 and 30 percent.



    FULL STORY ==========================================================================
    A gene called DOT1L appears to play a role in progression and severity
    of ovarian cancer, and inhibitors of the DOT1L enzyme may offer a new therapeutic approach for the disease, University of Alabama at Birmingham researchers say in a study published in the journal Oncogenesis.


    ==========================================================================
    The need is clear -- despite decades of work to develop new treatment modalities, the five-year survival of patients with advanced ovarian
    cancer is between 10 and 30 percent.

    Others have found that DOT1L is overexpressed in several cancer types,
    and recent clinical work has shown synergistic antiproliferative activity
    for a DOT1L inhibitor against MLL-rearranged leukemia.

    The UAB researchers, led by Romi Gupta, Ph.D., assistant professor
    of biochemistry and molecular genetics, now show that DOT1L promotes
    ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic
    pathways and blocking the programmed cell death called apoptosis.

    Gupta and colleagues first looked at data sets from patients. They found
    that DOT1L expression was significantly higher in tissues from ovarian
    cancer patients compared with tissues from healthy patients. Furthermore, patients with ovarian tumors that had high DOT1L expression showed
    shorter progression- free survival and shorter overall survival rates
    compared with patients whose ovarian tumors had lower DOT1L expression.

    DOT1L is a histone methyltransferase that epigenetically methylates
    the histone H3 lysine 79 in chromatin, and this alters gene expression
    in cells. The UAB researchers found that EPZ-5676 -- a DOT1L inhibitor
    that has been used in several clinical trials to treat MLL-rearranged
    leukemia -- was able to block the growth of ovarian cancer cells in
    culture. EPZ-5676 also significantly blocked subcutaneous ovarian cancer
    tumor growth in a mouse xenograft model.

    Mechanistically, DOT1L inhibition downregulated the expression of various
    genes that are required for biosynthetic pathways and reduced the levels
    of essential biosynthetic metabolites in the ovarian cancer cells. DOT1L inhibition also upregulated genes involved in programmed cell death, which increased apoptotic cell death for ovarian cancer cells in culture. The pharmacologic inhibition of DOT1L also upregulated expression of ligands
    for natural killer cells in some of the ovarian cancer cell lines tested.

    These gene expression changes seen in DOT1L inhibitor-treated cells thus suggest that DOT1L overexpression in ovarian cancer leads to plentiful
    supplies of the metabolites needed for rapid tumor growth and also
    protects against tumor cell death caused by apoptosis or natural killer
    cell attack.

    "Our results suggest that DOT1L might be a pharmacologically tractable
    drug target for ovarian cancer therapy," Gupta said. "It will also be
    useful in combination with other immunotherapeutic agents to further
    enhance their effectiveness in treating ovarian cancer." Co-authors with
    Gupta for the study, "Disruptor of telomeric silencing 1-like promotes
    ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic
    pathways and blocking apoptosis," are Suresh Chava, Suresh Bugide
    and Yvonne J.K. Edwards, UAB Department of Biochemistry and Molecular
    Genetics.

    Support came from National Institutes of Health grants CA230815-02
    and CA248913-01.

    ========================================================================== Story Source: Materials provided by
    University_of_Alabama_at_Birmingham. Original written by Jeff
    Hansen. Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Suresh Chava, Suresh Bugide, Yvonne J. K. Edwards, Romi
    Gupta. Disruptor
    of telomeric silencing 1-like promotes ovarian cancer tumor growth
    by stimulating pro-tumorigenic metabolic pathways and blocking
    apoptosis.

    Oncogenesis, 2021; 10 (7) DOI: 10.1038/s41389-021-00339-6 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2021/08/210805154731.htm

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