Targeting Cancer Stem Cells with Differentiation Agents as an Alternative to Genotoxic Chemotherapy for the Treatment of Malignant Testicular Germ Cell Tumors

SIMPLE SUMMARY: Testicular germ cell tumors (TGCTs) are the most common solid malignancy in young men. Fortunately, these tumors are highly curable with conventional genotoxic chemotherapy. However, because these chemotherapeutics have significant short- and long-term side effects, less toxic treatment options are desired. We report that thioridazine, an FDA-approved antipsychotic, differentiates embryonal carcinoma (EC) cells, the cancer stem cells of many malignant TGCTs, and suppresses their tumor propagating activity. Additionally, thioridazine treatment of mice with EC-containing neoplasms extends survival relative to untreated control mice. These findings identify thioridazine as a promising alternative or adjuvant to chemotherapy for the treatment of TGCTs. ABSTRACT: Testicular germ cell tumors (TGCTs) are exceptionally sensitive to genotoxic chemotherapy, resulting in a high cure rate for the young men presenting with these malignancies. However, this treatment is associated with significant toxicity, and a subset of malignant TGCTs demonstrate chemoresistance. Mixed nonseminomas often contain pluripotent embryonal carcinoma (EC) cells, the cancer stem cells (CSCs) of these tumors. We hypothesized that differentiation therapy, a treatment strategy which aims to induce differentiation of tumor-propagating CSCs to slow tumor growth, could effectively treat mixed nonseminomas without significant toxicity. The FDA-approved antipsychotic thioridazine and the agricultural antibiotic salinomycin are two drugs previously found to selectively target CSCs, and here we report that these agents differentiate EC cells in vitro and greatly reduce their tumorigenic potential in vivo. Using a novel transformed induced pluripotent stem cell allograft model and a human xenograft model, we show that thioridazine extends the survival of tumor-bearing mice and can reduce the number of pluripotent EC cells within tumors. These results suggest that thioridazine could be repurposed as an alternative TGCT treatment that avoids the toxicity of conventional chemotherapeutics.