Researchers have identified a therapeutic target called DDX3 whose inhibition not only prevents the growth of prostate cancer cells, it also increases their sensitivity to radiation therapy, both in culture and in animal models.
The study, “RK-33 radiosensitizes prostate cancer cells by blocking the RNA helicase DDX3,” published in Cancer Research, suggests that combining the novel DDX3 inhibitor RK-33 with radiation therapy may be a viable option to treat locally advanced prostate cancer.
Conventional treatments for prostate cancer include surgery, chemotherapy, radiation therapy, or active surveillance. Radiation therapy has been used effectively as a first-line treatment for locally advanced prostate cancer, but patients often develop resistance to radiation over time.
Therefore, additional drugs that make cancer cells more sensitive to radiation and that allow reduced radiation doses and radiation-induced side effects are urgently needed.
Looking for a means to reduce the side effects associated with high doses of radiation, Venu Raman, PhD, from the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center, worked together with Phuoc Tran, MD, PhD, also a member of the Kimmel Cancer Center.
They had previously found that DDX3 was highly expressed in a number of cancers, including breast, lung, colorectal, and prostate cancer, with higher levels of this protein corresponding to more aggressive cancers.
Inhibiting this protein with RK-33, a molecule developed by the researchers that binds to a region of DDX3 required for its activity, impaired the growth of lung and other cancer cells and seemed to function as a radiosensitizer.
Now, the researchers sought to assess if blocking DDX3 could also make prostate cancer cells more sensitive to radiation.
They started by examining samples from prostate cancer patients treated at the University Medical Centre Utrecht in the Netherlands. Consistent with previous findings in other cancers, the researchers found that the higher the expression of DDX3, the more aggressive the cancer. This was observed in cell cultures; of the 23 samples with a Gleason score higher than seven, eight had high levels of DDX3.
When the researchers used genetic approaches to halt DDX3 expression in prostate cancer cell lines that highly expressed this protein, they found their growth was reduced by half compared to cells expressing high levels of DDX3.
Importantly, when the DDX3 inhibitor RK-33 was used in animal models, the investigators found that it not only reduced tumor cell proliferation, it also worked synergistically with radiation therapy, killing up to four times more cancer cells than radiation therapy alone.
Given that no toxicity was observed in mice treated with RK-33, the researchers believe this drug could be a promising treatment approach for patients with cancers that express high levels of DDX3, increasing the effectiveness of radiation therapy at lower doses than currently used.
“A lot of work still needs to be done to develop this into a chemotherapy drug,” Raman said in a press release. “But based on our findings, we think it could fill an unmet need in making the most common treatment for prostate cancer more effective.”