Advanced prostate cancer has an unexpected weakness that can be targeted
by drugs
Researchers identified that SUCLA2-deficient prostate cancer cells can be selectively treated with thymoquinone

Date:
October 7, 2020
Source:
Kanazawa University
Summary:
Researchers reported that the SUCLA2 gene is frequently involved
in the deletion of the tumor suppressor gene RB1 in advanced
prostate cancer.

RB1 deletion makes cells resistant to hormone therapy but SUCLA2
deletion induces a metabolic weakness. The study showed that
thymoquinone selectively killed SUCLA2-deficient prostate cancer
cells in vitro and in vivo. The findings highlight a vulnerability
of advanced prostate cancer cells that can be targeted by drugs.



FULL STORY ==========================================================================
The compound thymoquinone (TQ) selectively kills prostate cancer cells at advanced stages, according to a new study published in Oncogene. Led by researchers at Kanazawa University, the study reports that prostate cancer cells with a deletion of the SUCLA2 gene can be therapeutically targeted.

SUCLA2-deficient prostate cancers represent a significant fraction of
those resistant to hormone therapy or metastatic, and a new therapeutic
option for this disease would have immense benefits for patients.


========================================================================== Hormone therapy is often chosen for the treatment of metastatic prostate
cancer but nearly half of patients develop resistance to the treatment
in as little as 2 years. A mutation in RB1, a tumor suppressor gene that
keeps cell growth under control, has been pegged as a particularly strong driver of treatment resistance and predicts poor outcome in patients.

"Mutations in tumor suppressor genes are enough to induce initiation and malignant progression of prostate cancer, but so far we haven't been
able to directly target these mutations with drugs to treat prostate
cancer," says the lead author Susumu Kohno. "We wanted to find a genetic aberration associated with that of a tumor suppressor gene which we
could target therapeutically." In the genome, SUCLA2 neighbors RB1. An analysis of prostate cancer cells showed that cells with a RB1 deletion
were also missing SUCLA2, pairing up the SUCLA2 deletion with the RB1
deletion present in advanced stage prostate cancer. Kohno and colleagues analyzed prostate cancer tissue and found that 11% of cases were missing
both SUCLA2 and RB1.

The researchers screened compounds to identify drugs that would
selectively kill cells with a SUCLA2 deletion. Out of around 2,000
compounds, TQ emerged as a hit compound. TQ already has known anti-cancer effects and was shown to be safe in a phase I clinical trial. Kohno and colleagues applied the TQ treatment to a mouse model of SUCLA2-deficient prostate cancer and TQ selectively suppressed tumor growth.

"These findings show that TQ treatment could be an effective therapy
for treating prostate cancer cells that harbor SUCLA2 deficiency" says
the senior author Chiaki Takahashi.

In a search of genetic databases from patients with prostate cancer,
the researchers found that the frequency of SUCLA2 loss was almost
perfectly aligned with RB1 loss at every disease stage -- meaning the
SUCLA2 deletion could identify people with prostate cancer needing
advanced therapy.

Finding this drug-targetable vulnerability opens a crack in the barrier
of treatment resistance for prostate cancer. More work needs to be done
to improve efficacy of TQ and identify patients that would benefit from
this type of treatment, but the compound provides a promising route for
new treatment options for advanced prostate cancer.


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


========================================================================== Journal Reference:
1. Susumu Kohno, Paing Linn, Naoko Nagatani, Yoshihiro Watanabe, Sharad
Kumar, Tomoyoshi Soga, Chiaki Takahashi. Pharmacologically
targetable vulnerability in prostate cancer carrying
RB1-SUCLA2 deletion. Oncogene, 2020; 39 (34): 5690 DOI:
10.1038/s41388-020-1381-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201007123053.htm

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