• Achilles' heel of high-risk multiple mye

    From ScienceDaily@1:317/3 to All on Thu Apr 7 22:30:40 2022
    Achilles' heel of high-risk multiple myeloma

    Date:
    April 7, 2022
    Source:
    National University of Singapore
    Summary:
    Chromosomal abnormalities are found in most multiple myeloma (MM)
    patients. While myeloma patients have generally benefited from the
    advancement of treatment modalities over the years, the treatment
    outcome for patients having two or more high-risk prognostic events
    remains poor.

    In a novel step forward, a research team has embarked on a study
    which aims to address the unmet clinical need in this group of
    patients.



    FULL STORY ========================================================================== Chromosomal abnormalities are found in most multiple myeloma (MM)
    patients.

    While myeloma patients have generally benefited from the advancement of treatment modalities over the years, the treatment outcome for patients
    having two or more high-risk prognostic events remains poor. In a novel
    step forward, a research team led by Professor Chng Wee Joo from the
    Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) embarked on a study which aims to address
    the unmet clinical need in this group of patients.


    ==========================================================================
    The deletion of chromosome 17p13 (17p13(del)) and the gain of
    chromosome 1q21 (1q21(gain)) are long-standing independent high-risk biomarkers. However, the biological significance underlying the poor
    outcome in MM patients having co- occurrence of both chromosomal
    abnormalities has never been interrogated.

    In the study recently published in Oncogene in February 2022, Prof Chng
    and his team uncovered that MM cells of patients harbouring concomitant 17p13(del) with 1q21(gain) have loss of functional p53 and NEIL1
    respectively, both of which are important DNA repair genes. MM cells of
    this high-risk patient group demonstrated defective DNA damage response
    (DDR) associated with high genomic instability signature and persistent activation of Chk1 pathway.

    Findings revealed that in the event of NEIL1 and p53 inactivation, cells
    would be highly dependent on the Chk1 pathway, suggesting a synthetic
    lethal relationship between p53-NEIL1-Chk1 abnormalities. Interestingly,
    this proof- of-concept study is one of the first in this high-risk
    myeloma patient subgroup.

    Their findings present the biological and therapeutic relevance of Chk1 inhibition in targeting DDR and genomic instability, both of which are characteristic traits of high-risk patients with co-occurrence of the two chromosomal abnormalities. More importantly, discovering the Achilles'
    heel of this disease has opened doors for more effective and novel
    treatment modalities to address an unmet medical need of myeloma.

    Moving forward, Prof Chng and his team are hoping to establish
    Chk1 inhibitors as the standard of care and targeted treatment for 17p13(del)-1q21(gain) high- risk patients. The team plans to further investigate the leverage of this genomic instability on the armamentarium
    of novel therapies in myeloma, including immune-based and cell therapy products.


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


    ========================================================================== Journal Reference:
    1. Phaik Ju Teoh, Omer An, Tae-Hoon Chung, Thamil Vaiyapuri,
    Anandhkumar
    Raju, Michal M. Hoppe, Sabrina H. M. Toh, Wilson Wang, Ming Chun
    Chan, Melissa J. Fullwood, Anand D. Jeyasekharan, Vinay Tergaonkar,
    Leilei Chen, Henry Yang, Wee Joo Chng. p53-NEIL1 co-abnormalities
    induce genomic instability and promote synthetic lethality
    with Chk1 inhibition in multiple myeloma having concomitant
    17p13(del) and 1q21(gain). Oncogene, 2022; 41 (14): 2106 DOI:
    10.1038/s41388-022-02227-8 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220407101045.htm

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