A new targeted therapy from Case Western Reserve University could treat advanced prostate cancer without the severe dry mouth that drives many patients to quit life-saving care. Early tests show strong tumor targeting with far less damage to salivary and tear glands.
For many men with advanced prostate cancer, one of the most promising treatments comes with a devastating tradeoff: it can leave them unable to eat, swallow or speak comfortably because of extreme dry mouth.
Researchers at Case Western Reserve University say they have developed a new version of that therapy that appears to keep its cancer-fighting power while sharply reducing the damage that causes this debilitating side effect.
The experimental treatment, described in the journal Molecular Imaging and Biology, targets the same protein on prostate cancer cells as current drugs but uses a redesigned molecule to home in on tumors and spare healthy glands.
The approach builds on a type of precision medicine known as radioligand therapy. In this treatment, a radioactive payload is attached to a targeting molecule that seeks out prostate-specific membrane antigen, or PSMA, a protein found in high concentrations on prostate cancer cells. Once the compound reaches the tumor, the radiation helps destroy the cancer from the inside.
Because it can selectively hunt down cancer cells throughout the body, PSMA-targeted radioligand therapy is often compared to a “smart bomb” in oncology. It has emerged as one of the most promising options for men with end-stage prostate cancer whose disease has spread and stopped responding to other treatments.
But there has been a major catch. PSMA is also present in salivary and tear glands. When the radioactive drug accumulates there, it can severely damage those tissues, leading to chronic dry mouth and dry eyes. For some patients, the constant pain, difficulty swallowing and trouble speaking become so severe that they stop treatment even when it is helping control their cancer.
“Various strategies to mitigate this side effect have been attempted with limited success,” James P. Basilion, a professor in the Department of Biomedical Engineering at Case Western Reserve and co-leader of the Cancer Imaging Program at the Case Comprehensive Cancer Center, said in a news release.
The Case Western Reserve team set out to redesign the targeting part of the drug so it would bind more tightly to prostate cancer cells and less to the glands that produce saliva and tears.
“Our study introduced a new PSMA-targeting ligand or molecule we call PSMA-1-DOTA with more favorable binding characteristics than existing treatments,” added Xinning Wang, a research associate professor in the Department of Biomedical Engineering and member of the Cancer Imaging Program.
The DOTA portion of the compound acts like a molecular clamp, holding radioactive metals securely so they can be delivered to specific targets in the body. By pairing DOTA with the newly engineered PSMA-1 molecule, the researchers created a compound that, in their tests, latched onto prostate cancer cells four times more strongly than current PSMA-targeted drugs.
In animal studies, PSMA-1-DOTA matched the tumor-killing effectiveness of standard radioligand therapy but caused far less damage to salivary and tear glands. The researchers report that this greatly reduced the risk of dry mouth and related complications, without sacrificing cancer control.
To see whether the lab findings would hold up in people, the team collaborated with clinicians at the Technical University of Munich in Germany. They tested PSMA-1-DOTA in a patient with metastatic prostate cancer, tracking where the compound traveled in the body.
The early human data lined up with the animal results: the new treatment concentrated in prostate cancer lesions while largely avoiding the salivary glands, suggesting it could help prevent the severe dry mouth that limits current therapies.
If those results are confirmed in larger studies, the impact on patient care could be significant. Today, doctors often reserve PSMA-targeted radioligand therapy for late stages of the disease, partly because of concern about long-term side effects.
“This breakthrough could fundamentally change prostate cancer care by transforming PSMA-targeted therapy from a ‘last resort’ option to an earlier intervention,” added Zhenghong Lee, a professor in the Department of Radiology and co-leader of the Cancer Imaging Program.
Being able to offer this type of targeted radiation earlier could give patients another powerful tool before their cancer becomes resistant to other treatments. It might also allow more men to stay on therapy long enough to gain the full benefit, without being forced to choose between quality of life and life-extending care.
The research team is now planning a clinical trial to further test safety, effectiveness and dosing in people. They expect to enroll about a dozen patients with prostate cancer in a study slated to begin late next year.
That trial will be an important next step in determining whether PSMA-1-DOTA can move from promising lab discovery to a new standard of care. If successful, it could mark a turning point in how doctors use targeted radiation against prostate cancer, offering patients a treatment that aims not only to extend life, but to preserve the everyday functions that make life livable.
Source: Case Western Reserve University