Novel therapeutic target in multiple myeloma

Date:
January 12, 2022
Source:
Institut Pasteur
Summary:
Multiple myeloma is a cancer of the bone marrow, with a life
expectancy of less than 5 years post-diagnosis. Proteasome
inhibitors, the therapeutic backbone of current treatments, are
very effective in treating newly diagnosed cancers but resistance
or intolerance to these molecules inevitably develop, leading to
relapses. While studying a neglected tropical disease , Buruli
ulcer, researchers discovered a novel therapeutic target for
multiple myeloma that could allow to bypass this resistance.



FULL STORY ========================================================================== Multiple myeloma is a cancer of the bone marrow, with a life expectancy of
less than 5 years post-diagnosis. Proteasome inhibitors, the therapeutic backbone of current treatments, are very effective in treating newly
diagnosed cancers but resistance or intolerance to these molecules
inevitably develop, leading to relapses. While studying a neglected
tropical disease, Buruli ulcer, researchers from the Institut Pasteur
and Inserm discovered a novel therapeutic target for multiple myeloma
that could allow to bypass this resistance. The results of this study
were published in EMBO Molecular Medicine on January 11th, 2022.


========================================================================== Multiple myeloma is a cancer caused by the abnormal proliferation
of plasma cells, white blood cells producing antibodies, in the bone
marrow. Scientists from the Institut Pasteur and Inserm, in collaboration
with the University of Paris and the Saint Louis Hospital (AP-HP)
describe a new mechanism to selectively kill these cancer cells.

Researchers in the Immunobiology of Infection Unit at the Institut Pasteur
made this discovery while working on a completely different disease:
Buruli ulcer.

This neglected tropical disease, caused by infection with a bacterium (Mycobacterium ulcerans), can provoke severe and irreversible skin
necrosis.

Lesions are due to bacterial production of a toxin called "mycolactone"
in infected skin. In 2016, this team discovered how mycolactone causes
the clinical manifestations of Buruli ulcer: by targeting the translocon (Sec61).

The translocon is a channel anchored in the wall of a cell compartment
called the endoplasmic reticulum that plays a crucial role in the
synthesis of a subset of proteins: those that are destined to be secreted
in the extracellular medium. The translocon controls the import of these proteins into the endoplasmic reticulum, and it is the main gateway
to the secretory pathway. By blocking Sec61, mycolactone retains these
proteins inside the cell and provokes their degradation by the proteasome,
a stressful process that can evolve towards programmed cell death.

Using murine models and tumors from patient biopsies, researchers
demonstrated that mycolactone is highly toxic to multiple myeloma cells, including those that have become resistant to proteasome inhibitors,
at doses that are non- toxic to normal cells. In addition, they showed
that mycolactone and proteasome inhibitors work in synergy, mutually potentiating their anti-cancer effects.

"This study provides the proof of concept that the translocon is a
new therapeutic target in multiple myeloma. The next step will be to
identify drug- like molecules inhibiting Sec61, which could constitute a
new treatment for this cancer. In addition, we aim to study whether this
target could be common to other cancers." explains Caroline Demangel,
head of the Immunobiology of Infection Unit at the Institut Pasteur.

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


========================================================================== Journal Reference:
1. Antoine Domenger, Caroline Choisy, Ludivine Baron, Ve'ronique Mayau,
Emeline Perthame, Ludovic Deriano, Bertrand Arnulf,
Jean‐Christophe Bories, Gilles Dadaglio, Caroline
Demangel. The Sec61 translocon is a therapeutic vulnerability
in multiple myeloma. EMBO Molecular Medicine, 2022; DOI:
10.15252/emmm.202114740 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220112105637.htm
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