Cornell researchers test antipsychotic drug on testicular tumors

A team of researchers at Cornell University has found that the common antipsychotic drug thioridazine suppresses the tumor activity of many malignant testicular germ cell tumors in laboratory mice. 

The drug targets the cancer stem cells and extends survival of the mice, compared to an untreated control group. These results hold promise for the use of thioridazine as an alternative to chemotherapies, which carry significant toxicity and to which a subset of testicular cancers may be resistant.

The work was published in a special issue of the journal Cancers, April 23. The authors are an interdisciplinary team from the Cornell University departments of biomedical sciences, microbiology and Immunology, and biomedical engineering. Dr. Robert S. Weiss is the corresponding author. 

Testicular germ cell tumors (TGCTs) make up nearly 95% of all testicular cancers, and are highly susceptible to conventional chemotherapy. The 5-year survival rate for conventional chemotherapy for TGCT is nearly 95%. 

However, there are some caveats to conventional treatment. 

First, 15-20% of those found to have metastatic TCGT at initial diagnosis (about 30% of all patients) suffer a relapse. Only half of these can then be saved, according to the authors. 

Second, chemotherapy often produces acute side effects including, nausea, vomiting, diarrhea and constipation. It also can be permanently debilitating. 

“As TCGT patients are relatively young and often cured,” the authors note, “survivors face significant long-term morbidity associated with chemotherapy, such as neurotoxicity, nephropathy, cardiovascular disease, pulmonary damage, secondary malignancies, metabolic syndrome, hypogonadism, psychosocial difficulties, and subfertility. Accordingly, less toxic and more efficacious alternatives to chemotherapy are needed.” 

How differentiation therapy works

Rather than killing the cancer cells, the concept behind this treatment, known as differentiation therapy, is to force the cells that have become cancerous back into a normal state of growth. The idea originated with the discovery that leukemia cells do not undergo a normal differentiation and maturation process. Instead, they behave somewhat like undifferentiated stem cells.

The more aggressively metastatic forms of testicular germ cell tumors, known as nonseminomas, are often composed of two types of cells. One type, the pluripotent embryonal carcinoma (EC) cells, behave like stem cells. These are the target of the differentiation therapy. The other type, the teratoma cells, are already differentiated. 

Earlier studies had found two agents that were able to selectively target cancer stem cells. These were the veterinary antiprotozoal drug, salinomycin, and the once-common antipsychotic drug, thioridazine. 

The new research shows that both drugs are able to differentiate the stem-cell-like embryonal carcinnoma (EC) cells in laboratory cultures (in vitro), and greatly reduce their tumor-causing potential in live animals (in vivo). 

As thioridazine is FDA-approved for human use, the researchers focused on this drug in further studies on laboratory mice. 

They made use of a mouse model, known as the human tumor xenograft, commonly used in cancer research. In this method, human tumor cells are transplanted into immunocompromised laboratory mice that do not reject human cells. They also employed a novel technique of transforming pluripotent stem cells. 

The results of careful and repeated laboratory trials showed that thioridazine “extends the survival of tumor-bearing mice and can reduce the number of pluripotent EC cells within tumors,” the authors state.

“These results suggest that thioridazine could be repurposed as an alternative TGCT treatment that avoids the toxicity of conventional chemotherapeutics,” they conclude.