Pancreatic cancer: Cellular process suggests path to new treatment
options

Date:
February 24, 2022
Source:
Charite' - Universita"tsmedizin Berlin
Summary:
Drug resistance is a major obstacle in the treatment of cancers. In
an aggressive type of pancreatic cancer, for instance, drug
resistance is associated with the suppression of programmed
cell death, which results in the uncontrolled growth of cancer
cells. Until recently, the process underlying this phenomenon had
remained unknown. A team of researchers has now elucidated the
way in which different factors interact in order to enable these
cancer cells to survive. They were able to show that inhibition
of a key protein limits cancer growth. The researchers' findings
may herald a new treatment target for aggressive cancers.



FULL STORY ==========================================================================
Drug resistance is a major obstacle in the treatment of cancers. In an aggressive type of pancreatic cancer, for instance, drug resistance is associated with the suppression of programmed cell death, which results
in the uncontrolled growth of cancer cells. Until recently, the process underlying this phenomenon had remained unknown. A team of researchers
from Charite' - - Universita"tsmedizin Berlin have now elucidated the
way in which different factors interact in order to enable these cancer
cells to survive. They were able to show that inhibition of a key protein limits cancer growth. The researchers' findings, which have been published
in PNAS, may herald a new treatment target for aggressive cancers.


==========================================================================
Some types of cancer are particularly difficult to treat, due to their
ability to evade existing therapies. Pancreatic cancer is one such
cancer - - specifically, an aggressive subtype known as pancreatic
ductal adenocarcinoma (PDAC). Every year, approximately 19,000 people in Germany develop pancreatic cancer. The most common reason for treatment resistance is the suppression of the process of programmed cell death,
known as apoptosis. Targeted treatment therefore requires the use of new treatment strategies. "In addition to identifying a new treatment target,
we were able to elucidate a mechanism which enables us to circumvent
cancer cell resistance. This enabled us to propose a new strategy for
the treatment of particularly aggressive forms of cancer," says PD
Dr. Matthias Wirth of Charite''s Department of Hematology, Oncology and
Cancer Immunology on Campus Benjamin Franklin.

Working alongside colleagues from other research organizations in Germany,
the United States and the Netherlands, PD Dr. Wirth and his team undertook
a detailed study of the processes involved in apoptosis. They discovered
that the NOXA protein -- which is a key proapoptotic factor -- appears to
be suppressed in particularly aggressive forms of pancreatic cancer. The mechanism responsible for this suppression had remained unknown until
now. "Our approach was therefore to identify drug candidates which might
be capable of unleashing NOXA's cancer-suppressing potential. Using an
unbiased drug screening experiment to systematically test substances in genetically altered cell lines, we were able to identify one effective substance," explains PD Dr. Wirth. He continues: "The substance in
question was an inhibitor of the transcription factor known as RUNX1,
which is usually present in large quantities in patients with pancreatic
cancer and is associated with an inferior prognosis." The researchers
performed a comprehensive series of genome-wide gene expression analyses
in order to identify gene activity. This enabled the researchers to show
that loss of the RUNX1 gene cancels the suppression of the NOXA protein,
which suggests that the RUNX1 protein prevents apoptosis, meaning it
has a cancer-promoting effect.

The researchers also found that NOXA gene activity is controlled
through spatial interaction with a distant, non-coding DNA sequence to
which the transcription factor RUNX1 can bind. As part of a nationwide collaboration, the researchers were then able to demonstrate the same apoptosis-inducing effect of RUNX1 inhibition in both a mouse model
and in organoids (cancer patient- derived, three-dimensional cell
cultures). Summing up the research, PD Dr.

Wirth says: "Our findings therefore direct our focus towards effective
RUNX1 inhibitors as a potential new option in the treatment of pancreatic cancer." He adds: "We are now investigating the degree to which this
newly discovered mechanism might translate to other types of cancers. Our
next step will be to test more substances, in particular ones already in clinical use. We hope this will enable us to uncover potential combination therapies which would then be tested in clinical studies and ultimately
expand the treatment options available to patients with cancer." ========================================================================== Story Source: Materials provided by
Charite'_-_Universita"tsmedizin_Berlin. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Josefina Doffo, Stefanos A. Bamopoulos, Hazal Ko"se, Felix Orben,
Chuanbing Zang, Miriam Pons, Alexander T. den Dekker, Rutger W. W.

Brouwer, Apoorva Baluapuri, Stefan Habringer, Maximillian Reichert,
Anuradha Illendula, Oliver H. Kra"mer, Markus Schick, Elmar
Wolf, Wilfred F. J. van IJcken, Irene Esposito, Ulrich Keller,
Gu"nter Schneider, Matthias Wirth. NOXA expression drives synthetic
lethality to RUNX1 inhibition in pancreatic cancer. Proceedings of
the National Academy of Sciences, 2022; 119 (9): e2105691119 DOI:
10.1073/pnas.2105691119 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220224112613.htm

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