Drug targets unexpected weakness in advanced prostate cancer

Prostate cancer is the second most common cancer in men and the fourth most commonly occurring cancer worldwide.

But all is not gloom about this disease as new research shows that there is a weakness in the disease profile that can be targeted by drugs to effectively kill it.

The compound thymoquinone 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 these cells with a deletion of the SUCLA2 gene can be therapeutically targeted.

The 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 two years.

A mutation in a tumour 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.

Researchers reported that the SUCLA2 gene is frequently involved in the deletion of a tumour suppressor gene—RB1—in advanced cases. According to findings, 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 the vulnerability of advanced prostate cancer cells that can be targeted by drugs

“Mutations in tumour 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,” according to the lead author Susumu Kohno.

“We wanted to find a genetic aberration associated with that of a tumour suppressor gene which we could target therapeutically.”

The researchers screened compounds to identify drugs that would selectively kill cells with a SUCLA2 deletion. Out of around 2,000 compounds, thymoquinone emerged as a hit compound.

The drug already has known anti-cancer effects and was shown to be safe in a phase I clinical trial. Kohno and colleagues applied the treatment to a mouse model of SUCLA2-deficient prostate cancer and thymoquinone selectively suppressed tumour growth.

“These findings show that thymoquinone treatment could be an effective therapy for treating prostate cancer cells that harbour SUCLA2 deficiency” according to the senior author Chiaki Takahashi.

In a search of genetic databases from patients with this illness, the researchers realized that 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 the efficacy of thymoquinone 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.

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