The drug triggers immune cells to attack prostate cancer

According to a new study targeting mouse and human cells, a single drug compound attacks difficult-to-treat prostate cancer
on multiple fronts at once.
According to new research from Washington University School of Medicine in St.
Louis, it triggers an immune cell attack, helps immune cells penetrate tumors, and cuts off tumors' ability to
burn testosterone for fuel.
The drug may offer a promising new strategy
for treating patients with tumors who do not respond to standard therapies.

Prostate cancer is notorious for eventually developing resistance to standard treatments that block or reduce testosterone, which is the driving force
behind the growth of these tumors.
Like many solid tumors, prostate cancer has proven to be tenacious resistant to new immunotherapies
.
The new immunotherapy aims to weaken the immune system's T cells, allowing them to fight cancer invaders
.
Immunotherapy — most commonly immune checkpoint inhibitors — can be very effective, but is limited to certain cancers, such as melanoma
.

Senior author Nupam P.
Mahajan, Ph.
D
.
, professor of surgery, said, "We need to develop better therapies for prostate cancer patients because these tumors are resistant to the hormone-based therapies that doctors rely on to treat these cancers.
" "Immunotherapy is currently the newest and most promising cancer treatment, but even so, immune checkpoint inhibitors do not do much for most solid tumors
, including prostate cancer.
This study was surprising because we found that the drug activated cancer-fighting T cells in a novel way, and it also increased the ability of T cells to
penetrate tumors.
This could lead to more effective strategies
for patients whose cancer is difficult to treat.
”

The drug, called (R)-9b, is a small molecule that blocks oncogenes, which cause cancer
.
The researchers initially attributed the drug's success in mouse studies to its ability to reduce or eliminate androgen receptors
in prostate cancer cells.
These receptors bind to testosterone and use hormones to promote tumor growth
.
This drug's ability to eliminate androgen receptors differs from standard drugs that lower testosterone levels in the body, as well as other drugs
that block the transcriptional regulation of androgen receptors.

But because the new drug is so effective, Mahjan and his colleagues suspect something else is wrong
.
This drug blocks a drug called ACK1.
The researchers developed a strain of mice that lacked the gene altogether to study what happens
when the gene is lost.
At first, the researchers were puzzled
by the mice.
Mice that lack the entire gene often have obvious problems
.
But these mice look fine
.
When researchers looked for tumor growth, they found very little
.
Modeling cancer in these animals is difficult
.

"In these mice, when we introduced cancer cells as usual, no traces
of tumors were found," Mahajan said.
Mahajan is also a research member
at Barnes-Jewish Hospital and Siteman Cancer Center at the University of Washington School of Medicine.
"In the few mice that developed tumors, the tumors were smaller
than those of wild-type mice.
This is the first clue
that important changes have occurred in mice that lack the gene.
We found that they are able to produce a powerful immune response
against cancer cells.
”

When different mice — mice with this gene — were implanted with human prostate tumors and given drugs that blocked the gene, it produced the same effect: lifting the brakes on the immune system, creating increased
levels of certain types of T cells that attack cancer.
The drug also adds signaling molecules that allow T cells to penetrate tumors and kill cancer cells
more efficiently.
These (R)-9b-treated mice had much smaller tumors than control mice
.

Given the drug's success in penetrating tumors, the researchers investigated whether adding immune checkpoint inhibitors to drug treatments would be more effective, simultaneously inhibiting T cells in multiple ways — but without such improvement
.

"Surprisingly, we found that immune checkpoint inhibitors are activating ACK1 pathways that we are shutting down with this drug compound," Mahajan said
.
"It's possible that immune checkpoint inhibitors don't work on these tumors because they're booting ACK1, which suppresses the immune response
.
" Similar to prostate cancer, ACK1 pathway activation can also be used for other cancers that do not respond to checkpoint inhibitors
.
However, these cancers may respond to (R)-9b, so we hope to study this drug
in other solid tumors as well.
" ”

Mahajan said that because of the nature of the gene blocked by the drug, it triggers multiple responses
.
Many genes have multiple roles in the human body, ACK1, and its role in androgen receptor expression and control of the immune system, making it an attractive target for cancer treatment, especially for solid tumors containing hormone-growing components, such as prostate and breast cancer
.

Mahajan worked with the University of Washington's Office of Technology Management/Technology Transfer to patent
the drug's use in cancer treatment.
His team is collecting data in order to apply to the Food and Drug Administration for permission to conduct clinical trials
of the drug in prostate cancer patients.

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