Immunotherapy Trial in Metastatic Urothelial Cancer Urothelial cancer, the fifth most common cancer in the United States, occurs in the urinary system (kidney, urinary bladder and accessory organs) and is the most common type of bladder cancer. For patients in which the disease has spread, or metastasized, to other sites, treatment has been mostly limited to chemotherapy. However, recent advances in immunotherapy have suggested that strategies to mobilize the immune system and attack tumor cells might be beneficial for advanced urothelial cancer. Oncologist Peter O’Donnell, MD, assistant pro­ fessor of medicine, led a multicenter phase Ib clin- ical trial, part of the larger KEYNOTE-012 basket trial, testing the immunotherapy pembrolizumab in patients with locally advanced or metastatic urothelial cancer. Pembrolizumab, an antibody against the PD-1 immune checkpoint protein, was given to patients whose tumors expressed PD-L1 (a partner protein for PD-1 and thought to be required for PD-1 blockade to be effective). Thirty-three patients were enrolled in the study, and the drug was generally well-tolerated. More than one-quarter of the patients showed an overall response, including three with a complete response and four with a partial response. Results from this trial indicate that pembrolizumab demon- strated promising anti-cancer activity and accept- able safety in advanced urothelial cancer patients and supports ongoing phase II and III studies of pembrolizumab in these patients. (Plimack et al., Lancet Oncol 18:212-220, 2017) The Origin of Ovarian Cancer Ovarian cancer only accounts for about 1.3 percent of new cancer cases each year, but less than half of patients survive for five years after diagnosis because it is frequently diagnosed in late stages after it has already metastasized, or spread to other organs. Whether these tumors actually originate in the ovaries or fallopian tubes has been poorly understood, but is important in terms of understanding their behavior and blocking tumor spread. A team led by Ernst Lengyel, MD, PhD, Arthur L. and Lee G. Herbst Professor of Obstetrics and Gynecology, and involving Samuel Volchenboum, MD, PhD, associate professor of pediatrics, and S. Diane Yamada, MD, Joseph Bolivar DeLee Professor of Obstetrics and Gynecology, addressed this issue by DNA sequencing to detect genetic mutations in samples of serous tubal intraepithelial carcinomas (STIC), ovarian, fallopian tube, and abdominal tumors from patients, representing the progression from early to later cancers. The team found that STIC lesions in the fallopian tubes do not necessarily mean the cancer is isolated to that location. While the study found that STIC were precursor lesions in half of the patients, those lesions in 25 percent of patients were actu- ally metastases that had spread from another location in the abdomen. Further analyses using an innovative tissue culture model revealed that high-grade serous ovarian cancer (HGSOC) tumor cells can implant in the fallopian tubes and mimic STIC lesions. This finding could impact treatment protocols and suggests that the origin of gyneco- logic cancers isn’t always straight forward, and may differ from patient to patient. (Eckert et al., Cancer Discov 6:1342-1351, 2016) Research Highlights (continued) OF THE PATIENTS SHOWED AN OVERALL RESPONSE > 1/4 Research 8 PATHWAYS TO DISCOVERY SPRING 2017