Promising approach against treatment-resistant cancer

Date:
March 7, 2022
Source:
Albert Einstein College of Medicine
Summary:
A research team has devised a novel and highly promising strategy
for overcoming a key cause of cancer deaths: the ability of cancer
cells to thrive in the face of chemotherapy drugs designed to
destroy them.



FULL STORY ==========================================================================
A research team led by scientists at Albert Einstein College of Medicine
has devised a novel and highly promising strategy for overcoming a key
cause of cancer deaths: the ability of cancer cells to thrive in the
face of chemotherapy drugs designed to destroy them.


==========================================================================
As described in the March 7 issue of Nature Communications, investigators
used a two-drug combination to achieve chemotherapy's goal:to make cancer
cells self-destruct via the biological process known as apoptosis,
often referred to as programmed cell death. The treatment worked againsthumancancer cell lines that resisted apoptosis despite exposure
to different types of chemotherapy, and also against apoptosis-resistant
human tumors implanted in mice (i.e., xenograft mouse models).

"Targeted therapies that home in on specific genetic vulnerabilities
of cancers have vastly improved treatment in recent years, but not
everyone has benefited," said Evripidis Gavathiotis, Ph.D., professor
of biochemistry and of medicine at Einstein, co-leader of the Cancer Therapeutics Program at the NCI- designated Albert Einstein Cancer Center,
and corresponding author on the paper. "We need new, broadly active
therapies that can attack a range of cancers while causing fewer side
effects than current treatments, and we hope our new therapeutic strategy
will prove to be a viable option." Eliminating Unwanted Cells The body
relies on apoptosis for getting rid of unwanted cells -- excess cells
pruned during embryological development, for example, and damaged cells
that need to be removed so they don't survive to develop into cancer
cells. Both chemotherapy and radiation rely on damaging cancer cells
severely enough that they'll undergo apoptosis -- which, unfortunately,
does not always happen.

Every cell in the body contains the seeds of its own destruction: some
two dozen apoptotic proteins that engage in a life-or-death balancing
act. Some proteins stimulate apoptosis (pro-apoptotic proteins), while
others block the process (anti-apoptotic proteins). DNA damage, for
example, tips the balance in favor of cell death -- causing the cell
to express and activate pro-apoptotic proteins that ultimately kill
the cell by poking holes in its mitochondria. The new drug combination discovered by Dr. Gavathiotis and colleagues kills apoptosis-resistant
cancer cells by boosting the active form of one pro- apoptotic protein
in particular: BAX, dubbed the "executioner protein." Enhancing the "Executioner Protein"


==========================================================================
In 2012, Dr. Gavathiotis discovered the first small, human-made molecule capable of directly activating BAX. In their new study, he and his team evaluated whether BTSA1.2 -- their third-generation BAX activator --
would prove effective against a diverse group of 46 human blood and
solid tumor cell lines, including non-small cell lung cancer, breast, colorectal, pancreatic, melanoma, leukemia, and lymphoma cell lines. Most
of those cell lines had resisted all pro-apoptotic drugs developed so far.

BTSA1.2 did not perform impressively against several solid-tumor cell
lines.

The problem: Even as BTSA1.2 was increasing levels of active pro-apoptotic
BAX in solid-tumor cells, an anti-apoptotic protein called BCL-XL
was neutralizing BAX. The researchers then devised a novel strategy
for killing apoptosis- resistant cancer cells: Combine BAX-boosting
BTSA1.2 with Navitoclax, an investigational pro-apoptotic cancer drug
that inhibits BCL-XL.

The combination of BTSA1.2 and Navitoclax proved to be a
game-changer. When Dr.

Gavathiotis and colleagues, led by co-first author Andrea Lopez, Ph.D.,
tested the drug duo against the 46 cell lines, it packed a one-two punch,
with BTSA1.2 boosting active BAX to toxic levels in cancer cells,
and Navitoclax acting as BAX's bodyguard by preventing BCL-XL from
neutralizing BAX.

Limiting Side Effects The two orally administered drugs were then
tested against apoptosis-resistant tumor xenografts -- in this case,
mice implanted with tumor cells from a colorectal-cancer cell line that
had resisted BTSA1.2 and Navitoclax as individual drugs but had succumbed
to their combined use. The in vivo experiment produced similar results:
After xenografts were established, the mice were treated with BTSA1.2, Navitoclax, or the two drugs combined.

Individually, each drug had limited effectiveness in reducing
tumor growth, while combining them significantly suppressed tumor
growth, indicating that the two drugs act synergistically to defeat apoptosis-resistant tumors.

"Equally important, mice receiving the two-drug combination tolerated
it remarkably well," noted Dr. Gavathiotis. "Moreover, analysis of the
treated mice showed that healthy cells were not affected by the two-drug combination - - likely making it safer than standard chemotherapies,
which are toxic to all dividing cells, both cancerous and normal."
The study is titled "Co-targeting of BAX and BCL-XL proteins broadly
overcomes resistance to apoptosis in cancer." Other Einstein authors
are co-first author Denis E. Reyna, Ph.D., Nadege Gitego, Felix Kopp,
Lars Ulrik Nordstro/m, and Swathi-Rao Narayanagari. Additional authors
include Hua Zhou and Aristotelis Tsirigos at NYU Langone Health and
School of Medicine, Miguel A. Miranda-Roman and Ping Chi at Memorial
Sloan Kettering Cancer Center, and Eduardo Vilar at The University of
Texas MD Anderson Cancer Center. Einstein has licensed the BAX activator technology to BAKX Therapeutics Inc., which plans to commercialize the technology further to benefit patients. Dr. Gavathiotis is a co-founder
and scientific advisor of BAKX Therapeutics, Inc.

Studies were supported by the Pershing Square Sohn Cancer Research
Alliance, NCI grant 2R01CA178394, and the Irma T. Hirschl Trust Career
Award. Partial support was also provided by NCI grant P30 CA013330,
1S10OD01630 and a NYSTEM grant to the Einstein Stem Cell Isolation and Xenotransplantation Facility.

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


========================================================================== Journal Reference:
1. Andrea Lopez, Denis E. Reyna, Nadege Gitego, Felix Kopp, Hua
Zhou, Miguel
A. Miranda-Roman, Lars Ulrik Nordstro/m, Swathi-Rao Narayanagari,
Ping Chi, Eduardo Vilar, Aristotelis Tsirigos, Evripidis
Gavathiotis. Co- targeting of BAX and BCL-XL proteins broadly
overcomes resistance to apoptosis in cancer. Nature Communications,
2022; 13 (1) DOI: 10.1038/ s41467-022-28741-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220307113102.htm

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