Research Reveals Drug Targets for Malignant Prostate Cancer

According to a new study published on Oncogene, the compound thymoquinone (TQ) selectively kills prostate cancer cells in the late stages. Led by researchers at Kanazawa University, the study reported that prostate cancer cells with the SUCLA2 gene deletion can be used as therapeutic targets. Prostate cancer lacking SUCLA2 accounts for the majority of hormone therapy or metastatic resistance, so new treatment options for this disease will bring huge benefits to patients.

 

Hormone therapy is usually chosen to treat metastatic prostate cancer, but nearly half of patients become resistant to the therapy in just 2 years. RB1 is a tumor suppressor gene that controls cell growth. One of its mutations is considered to be a particularly powerful driving force for treatment resistance and can be used to predict adverse prognostic reactions in patients.

 

Susumu Kohno said: “Mutations in tumor suppressor genes are sufficient to induce the occurrence and malignant progression of prostate cancer, but so far, we have not been able to directly target these mutations with drugs to treat prostate cancer. Therefore, we wanted to find a tumor suppressor gene-related genetic aberrations and start treatment.”

 

 

In the genome, SUCLA2 is adjacent to RB1. Analysis of prostate cancer cells showed that cells with RB1 deletion also lack SUCLA2, matching the SUCLA2 deletion with the RB1 deletion present in advanced prostate cancer. Kohno and colleagues analyzed prostate cancer tissue and found that both SUCLA2 and RB1 were missing in 11% of cases.

 

The researchers screened the compound library to identify drugs that can selectively kill cells with SUCLA2 deletion. Among about 2,000 compounds, TQ became a popular candidate. TQ has known anti-cancer effects and has been proven safe in phase I clinical trials. Kohno and colleagues applied TQ therapy to a mouse model of SUCLA2-deficient prostate cancer. TQ selectively inhibited tumor growth.

 

Author Chiaki Takahashi said: “These findings suggest that TQ therapy may be an effective treatment for prostate cancer cells with SUCLA2 deficiency.”

 

When searching genetic databases from prostate cancer patients, the researchers found that at each disease stage, the frequency of SUCLA2 deletions was almost exactly the same as RB1 deletions-which means that SUCLA2 deletions can identify prostate cancer patients who need advanced treatment.

 

The discovery of this drug-targetable vulnerability has opened a new door to the treatment of resistance to prostate cancer. More work needs to be done to improve the efficacy of TQ and identify patients who can benefit from such treatments, but the compound provides a promising approach for new treatment options for advanced prostate cancer.

 

 

Reference

Susumu Kohno et al, Pharmacologically targetable vulnerability in prostate cancer carrying RB1-SUCLA2 deletion, Oncogene (2020). DOI: 10.1038/s41388-020-1381-6