Determinants of Testicular Germ Cell Tumor Platinum Sensitivity and Resistance

Testicular cancers are the most common solid malignancy in adolescents and young males.  They are unusually responsive to platinum (Pt)-containing chemotherapeutic drugs even when widely metastatic. Nevertheless some patients do not respond to initial therapy, and others with a good initial response become resistant to treatment. Why this type of tumor is so responsive to initial Pt drug treatment, and how it becomes resistant during therapy remain major questions in the field.  The proteins that transport copper into and out of cells have now been identified as affecting platinum drug uptake and tumor killing in other tumor types.  As of yet, no one has examined whether these have any role in testicular cancer despite evidence that copper is uniquely regulated in the testes. The overall goal of this project is to identify major determinants of Pt drug sensitivity in testicular cancer tumors, and how these change during the development of resistance.  My hypothesis is that the copper transport proteins are responsible for Pt drug uptake and processing in these tumors, and that alterations in their function lead to resistance.  Using testicular cancer cell lines I will determine whether copper transporter levels change during the development of resistance and effects Pt drug and copper uptake. I will explore the ability of drugs that alter cellular copper levels, or prevent the degradation of the major Pt drug influx transporter, to increase tumor cell killing. The results of these studies are expected to provide insight regarding novel pharmacologic strategies for preventing or overcoming Pt drug resistance in patients with testicular cancer.