An experimental drug appears to pack a one-two punch against some prostate cancers, significantly slowing the increase of cancer cells and making them more vulnerable to radiation.
The drug, tested in laboratory cell cultures and animals, works by targeting abnormally high levels of a protein linked to cancer growth. The findings could advance the search for new combination treatments that make radiation safer and more effective against prostate cancer.
The disease is the most common non-skin cancer in men and the second-leading cause of cancer-related deaths in men in the United States.
“A lot of work still needs to be done to develop this into a chemotherapy drug,” says Venu Raman, associate professor of radiology and radiological science and of oncology at the Johns Hopkins University School of Medicine. “But based on our findings, we think it could fill an unmet need in making the most common treatment for prostate cancer more effective.”
Radiation is a first-line therapy and generally is considered for all but the most advanced of the nearly 200,000 cases of prostate cancer diagnosed each year in the United States. Some of these cancers, however, become resistant to radiation treatment over time, Raman says.
In a search for ways to extend the value of radiation and limit collateral damage to healthy tissue from high radiation doses, Raman worked with Phuoc Tran, a radiation oncologist and, like Raman, a member of the Johns Hopkins Kimmel Cancer Center.
They and colleagues from Johns Hopkins and University Medical Centre Utrecht had earlier discovered that a protein called DDX3 appears to be “dysregulated” in many cancers, including breast, lung, colorectal, sarcoma, and prostate. The researchers found that the more aggressive the cancer, the higher the expression of this protein, which helps maintain cellular stability.
The researchers designed a molecule—called RK-33—to disrupt DDX3’s function by locking onto a portion of the protein. They have shown in cell cultures that adding RK-33 to malignant lung and other cancerous cells that highly express DDX3 slowed or halted multiplication of the cancer cells.
The cells’ ability to form colonies also was impaired. RK-33 also appeared to be a radiosensitizer, making the destructive effects of radiation in the cancer cells more pronounced.
In the latest study, published in the journal Cancer Research, scientists examined prostate cancer tissue samples from University Medical Centre Utrecht. As in earlier studies, the investigators found that the higher the expression of DDX3, the more aggressive the cancer.
Incubating cultured cancer cells with RK-33 suppressed DDX3 in cells that had highly expressed it, hampering their ability to multiply. When researchers combined the drug with radiation, the effects were synergistic, killing from two to four times more cells than radiation alone.
Next, the researchers tested the effects of RK-33 and radiation in mice that had been injected with human prostate cancer cells that highly express DDX3. The animals formed tumors within a few weeks. Together, Raman says, this dual-mode treatment produced cell-killing results that paralleled their experiments in cell cultures.
The experimental drug appears to have no toxicity in mice, Raman says, suggesting that it could be promising for use in humans. Compounds based on RK-33, he says, might have value in treating a broad array of cancers that highly express DDX33. The drug may make conventional radiation doses more effective or improve the killing ability of lower doses.
Source: Johns Hopkins University