Drugs showing promise in cancer trials reduce scarring for scleroderma
The findings could lead to repurposing drugs for patients with the sometimes-fatal condition

Date:
May 9, 2022
Source:
Michigan Medicine - University of Michigan
Summary:
Epigenetic drugs that have shown promise in cancer trials
significantly reduce scarring in the cells of patients with
scleroderma, a new study shows. Results reveal that drugs that
inhibit BRD4, known to play a role in cancer, also affect fibrosis
in scleroderma. Researchers tested BRD4 inhibitors on the skin
fibroblasts of scleroderma patients and in mouse models of skin
fibrosis, finding that the treatment stopped scarring in both
human-derived cells and in animals.



FULL STORY ========================================================================== Epigenetic drugs that have shown promise in cancer trials significantly
reduce scarring in the cells of patients with scleroderma, an incurable
and life- threatening autoimmune disease, a new study shows.


========================================================================== Scleroderma is a chronic disease that affects the immune system, causing
a buildup of scar-like tissues in the skin and internal organs known
as fibrosis.

This process occurs when cells that make up connective tissue, called fibroblasts, produce too much collagen that causes the skin and organs
of patients to harden -- resulting in tissue damage and organ failure.

In a recent study, Michigan Medicine researchers focused on BETs,
which are proteins that regulate gene expression by binding to
modifications on proteins around which DNA wraps, a process called
epigenetic regulation. Drugs targeting BETs, specifically an isoform
called BRD4, have been developed by various pharmaceutical companies
for cancer treatment.

Results published in JCI Insight reveal that drugs that inhibit
BRD4, known to play a role in cancer, also affect fibrosis in
scleroderma. Researchers tested BRD4 inhibitors on the skin fibroblasts of scleroderma patients and in mouse models of skin fibrosis. They found that
the treatment stopped scarring in both human-derived cells and in animals.

The inhibitors used by Michigan Medicine researchers have shown promise
for treating various cancers in preclinical studies. Specifically,
one drug used in the recent study, called AZD5153, is being tested in
a Phase I clinical trial for sarcomas and lymphomas.

"Through this study, we have uncovered a new class of epigenetic drugs
that can be used in scleroderma fibrosis," said Pen-Suen Tsou (Eliza),
Ph.D., senior author of the paper and a rheumatology researcher at
Michigan Medicine. "If we can repurpose these drugs and get them through development more quickly, we can provide faster relief for patients who struggle with debilitating symptoms of this autoimmune disease. The
process can typically take around 10 years, but our patients cannot
wait that long." The study is a collaborative effort with Michigan
Medicine's Scleroderma Program. Tsou's team also found that a calcium
signaling protein, called CaMKII, affects fibrosis in scleroderma,
which researchers had previously not seen.

"Right now, we are doing some follow up studies to see if inhibitors
of this protein can block scarring for scleroderma," Tsou said. "This
opens up a brand- new direction for us to offer a novel target for
this disease." Additional authors include: Sirapa Vichaikul, B.S.,
Mikel Gurrea-Rubio, Ph.D., M. Asif Amin, M.D., Phillip L. Campbell,
B.S., Qi Wu, Ph.D., Megan N.

Mattichak, William D. Brodie, Pamela J. Palisoc, B.S., Mustafa Ali, B.S.,
Sei Muraoka, M.D., Ph.D., Jeffrey H. Ruth, Ph.D., Ellen N. Model, B.S.,
Dallas M.

Rohraff, B.S., M.P.H., Jonatan L. Hervoso, B.S., Yang Mao-Draayer, M.D.,
Ph.D., David A. Fox, M.D., Dinesh Khanna, M.B.B.S., M.Sc., all of Michigan Medicine, and Amr H. Sawalha, M.D., University of Pittsburgh.


========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Noah
Fromson. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Sirapa Vichaikul, Mikel Gurrea-Rubio, M. Asif Amin, Phillip
L. Campbell,
Qi Wu, Megan N. Mattichak, William D. Brodie, Pamela J. Palisoc,
Mustafa Ali, Sei Muraoka, Jeffrey H. Ruth, Ellen N. Model, Dallas
M. Rohraff, Jonatan L. Hervoso, Yang Mao-Draayer, David A. Fox,
Dinesh Khanna, Amr H.

Sawalha, Pei-Suen Tsou. Inhibition of bromodomain extraterminal
histone readers alleviates skin fibrosis in experimental models
of scleroderma.

JCI Insight, 2022; 7 (9) DOI: 10.1172/jci.insight.150871 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220509162807.htm

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