Researchers identify new drug target for blood cancer, potentially solid tumors
Findings are being used to create a clinical trial for patients with myelodysplastic syndrome

Date:
October 7, 2021
Source:
The Mount Sinai Hospital / Mount Sinai School of Medicine
Summary:
Researchers have shown for the first time how mutations affecting
a cellular process called RNA splicing alter cells to develop
myelodysplastic syndrome (MDS) and other hematologic malignancies
and solid tumors.



FULL STORY ========================================================================== Mount Sinai and UC San Diego researchers have shown for the first time
how mutations affecting a cellular process called RNA splicing alter
cells to develop myelodysplastic syndrome (MDS) and other hematologic malignancies and solid tumors, according to a study published in Cancer Discovery in October.


========================================================================== Their research found that these mutations produce an alternative version
of the protein created by the gene GNAS.This protein can be targeted
by drugs already approved by the Food and Drug Administration for
treating other cancers, and therefore could be a good target in MDS. The researchers are creating a clinical trial to test these drugs, known as
MEK inhibitors and named for the proteins they inhibit to stop cancer.

MDS is a rare blood cancer that has no effective treatments and a poor prognosis. The mutations investigated in this study, however, are also
found in other cancers, which extends the possible applications of
these findings.

"This is the first study to discover that the altered protein created
by GNAS is increased in cells with these mutations in MDS, and this
results in the activation of processes that would render the cancer
cells vulnerable to the MEK inhibitors," said co-senior author Eirini Papapetrou, MD, PhD, Associate Professor of Oncological Sciences at
The Tisch Cancer Institute. "The discovery that we can try to use MEK inhibitors in this cancer is also a first, and our findings also support
future drug development to target GNAS, identified in this study."
Papapetrou led the study with Gene Yeo, PhD, professor at UC San Diego
School of Medicine. The researchers generated models of the mutations
using stem cells, in order to study them in a physiological genetic
context. They then turned the engineered cells into hematopoietic
progenitor cells -- which are the relevant cell type in blood cancers --
and performed splicing and RNA binding analyses.

"This work integrates isogenic models of disease with cutting-edge
RNA-omics to converge onto a new target for MDS," Yeo said.

These analyses allowed the team to identify high-confidence targets and
to identify the driver of the disease. The team showed that MDS cells
from the model as well as cells from MDS patients with these mutations
were sensitive to treatment with MEK inhibitors.

========================================================================== Story Source: Materials provided by The_Mount_Sinai_Hospital_/_Mount_Sinai_School_of Medicine. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Emily C Wheeler, Shailee Vora, Daniel Mayer, Andriana G Kotini,
Malgorzata Olszewska, Samuel S. Park, Ernesto Guccione, Julie
Teruya- Feldstein, Lewis Silverman, Roger K Sunahara, Gene
W Yeo, Eirini P Papapetrou. Integrative RNA-omics discovers
GNAS alternative splicing as a phenotypic driver of splicing
factor-mutant neoplasms. Cancer Discovery, 2021; candisc.0508.2021
DOI: 10.1158/2159-8290.CD-21-0508 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211007103345.htm

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