New study examines `Achilles heel' of cancer tumors, paving the way for
new treatment strategies

Date:
August 30, 2021
Source:
University of British Columbia
Summary:
Researchers have uncovered a weakness in a key enzyme that solid
tumor cancer cells rely on to adapt and survive when oxygen levels
are low.



FULL STORY ========================================================================== Researchers at the University of British Columbia's faculty of medicine
and BC Cancer Research Institute have uncovered a weakness in a key
enzyme that solid tumour cancer cells rely on to adapt and survive when
oxygen levels are low.


==========================================================================
The findings, published today in Science Advances, will help researchers develop new treatment strategies to limit the progression of solid
cancer tumours, which represent the majority of tumour types that arise
in the body.

Solid tumours rely on blood supply to deliver oxygen and nutrients to
help them grow. As the tumours advance, these blood vessels are unable to provide oxygen and nutrients to every part of the tumour, which results
in areas of low oxygen. Over time, this low-oxygen environment leads to
a buildup of acid inside the tumour cells.

To overcome this stress, the cells adapt by unleashing enzymes that
neutralize the acidic conditions of their environment, allowing the
cells to not only survive, but ultimately become a more aggressive form
of tumour capable of spreading to other organs. One of these enzymes is
called Carbonic Anhydrase IX (CAIX).

"Cancer cells depend on the CAIX enzyme to survive, which ultimately
makes it their 'Achilles heel.' By inhibiting its activity, we can
effectively stop the cells from growing," explains the study's senior
author Dr. Shoukat Dedhar, professor in UBC faculty of medicine's
department of biochemistry and molecular biology and distinguished
scientist at BC Cancer.

Dr. Dedhar and colleagues previously identified a unique compound, known
as SLC-0111 -- currently being evaluated in Phase 1 clinical trials --
as a powerful inhibitor of the CAIX enzyme. While pre-clinical models of breast, pancreatic and brain cancers have demonstrated the effectiveness
of this compound in suppressing tumour growth and spread, other cellular properties diminish its effectiveness.

In this study, the research team, which included Dr. Shawn Chafe,
a research associate in Dr. Dedhar's lab, together with Dr. Franco
Vizeacoumar and colleagues from the University of Saskatchewan, set out
to examine these cellular properties and identify other weaknesses of the
CAIX enzyme using a powerful tool known as a genome-wide synthetic lethal screen.This tool looks at the genetics of a cancer cell and systematically deletes one gene at a time to determine if a cancer cell can be killed
by eliminating the CAIX enzyme together with another specific gene.

According to Dr. Dedhar, the results of their examination were surprising
and point to an unexpected role of proteins and processes that control
a form of cell death called ferroptosis. This form of cell death
happens when iron builds up and weakens the tumour's metabolism and
cell membranes.

"We now know that the CAIX enzyme blocks cancer cells from dying as a
result of ferroptosis," says Dr. Dedhar. "Combining inhibitors of CAIX, including SLC- 0111, with compounds known to bring about ferroptosis
results in catastrophic cell death and debilitates tumor growth."
There is currently a large international effort underway to identify
drugs that can induce ferroptosis. This study is a major step forward
in this quest.

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


========================================================================== Journal Reference:
1. Shawn C. Chafe, Frederick S. Vizeacoumar, Geetha Venkateswaran,
Oksana
Nemirovsky, Shannon Awrey, Wells S. Brown, Paul C. McDonald,
Fabrizio Carta, Andrew Metcalfe, Joanna M. Karasinska, Ling Huang,
Senthil K.

Muthuswamy, David F. Schaeffer, Daniel J. Renouf, Claudiu
T. Supuran, Franco J. Vizeacoumar, Shoukat Dedhar. Genome-wide
synthetic lethal screen unveils novel CAIX-NFS1/xCT axis as a
targetable vulnerability in hypoxic solid tumors. Science Advances,
2021; 7 (35): eabj0364 DOI: 10.1126/sciadv.abj0364 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210830100009.htm

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