Urine proteomics to discover prognostic biomarkers and improved therapeutic targets for kidney tumors
Discovery of biomarkers for improved precision in oncology remains a critical problem. This is particularly pressing for cancers that currently lack adequate markers for stratification of chemotherapy and targets for improved approaches to overcome chemotherapy resistance. An additional conundrum in the field is how tumors that can be cured with chemotherapy can in some patients be chemotherapy resistant.
In a long-term collaboration with the Children’s Oncology Group, Hanno Steen, Elizabeth Mullen and many colleagues, and led by Michael Ortiz, we now describe a new approach for the discovery of urine biomarkers for kidney tumors, including Wilms tumor, the most common childhood kidney tumor. Using urine proteomics, we now provide a comprehensive profile of urinary biomarkers for most of kidney tumors, including Wilms tumors, renal rhabdoid tumors, kidney clear cell sarcomas, and renal cell carcinomas. In particular, we found new markers associated with Wilms tumor relapse, and confirmed the prognostic significance of urine prohibitin in multiple independent patient cohorts. Using functional genetic experiments, we found that overexpression of prohibitin is both necessary and sufficient to confer resistance to diverse chemotherapy drugs. This involved an unanticipated mechanism of aberrant apoptotic cytochrome c release through dysregulation of mitochondrial cristae structure, providing an explanation for the abnormal mitochondrial morphology first noted in Wilms tumors more than 50 years ago.
These findings define urine prohibitin as a potential clinical biomarker to improve therapy stratification and enable non-invasive monitoring of response and early disease relapse. In addition, our study reveals a general mechanism of chemotherapy resistance that is expected to have broad significance, given the prevalence of prohibitin overexpression across many cancer types.