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NIH grant 1P50CA310825-01: SPORE in Bladder Cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Jonathan Eric Rosenberg. Award: $2491899.
Start: 2026-09-18T00:00:00.
The past 10 years have witnessed a significant evolution in the systemic treatment of patients with urothelial cancer. Successful clinical trials have resulted in FDA approval of novel therapies spanning three mechanistically distinct drug classes: immune checkpoint inhibitors (anti-PD-1/PD-L1 antibodies), antibody-drug conjugates (anti-NECTIN4, anti-HER2 ADCs), and kinase inhibitors (FGFR kinase inhibitors). The combination of the NECTIN4-targeted ADC enfortumab vedotin (EV) plus the anti-PD-1 antibody pembrolizumab (EV+P) has also supplanted chemotherapy as initial systemic therapy for most patients with locally advanced and metastatic urothelial cancer. The translational objective of this MSK SPORE in Bladder Cancer is to build on recent improvements in clinical outcomes for patients with urothelial cancer across the disease spectrum by 1) elucidating the role of tumor and immunologic heterogeneity in mediating resistance to immunotherapies and ADCs, and 2) minimizing the morbidity of treatment through the development and validation of tissue-based and noninvasive predictive biomarkers. To pursue these translational objectives, we have assembled a multidisciplinary team with complementary expertise in the clinical management of urothelial cancer, immunology and antibody engineering, molecular pathology, cancer genetics, computational biology, and biostatistics. Our translational aims will be pursued through three projects, which, together with the Developmental Research and Career Enhancement programs, address all clinical states of urothelial cancer. Project 1 will identify immune-mediated mechanism of durable response and resistance to EV+P. Project 2 will study the effects of agonist anti-CD40 antibodies on the host immune response to guide the development of novel immune-based combinations. Project 3 will examine the role of lineage plasticity and other forms of phenotypic plasticity in mediating EV+P resistance and identify novel therapeutic approaches for bladder cancers with variant histologic features. Functional studies will be performed using mouse models, as current in vitro models (such as cell lines and organoids), computational models, and existing real-world data cannot model the complex adaptive response of immune and cancer cells to immune checkpoint inhibitors and ADCs. All three projects will be supported by the Biospecimen Repository and the Biostatistics & Bioinformatics Core, which will assist with the preparation and analysis of tumor and blood samples and with the association of molecular features with treatment response data, respectively. An Administrative Core will ensure integration across the entire SPORE program and facilitate data sharing and external collaborations. Finally, developmental research projects and career mentorship have been fully integrated into the SPORE program to ensure that new and established investigators with innovative approaches can advance our long-term objectives of enhancing patient outcomes while reducing the morbidity of treatment and ultimately eliminating urothelial cancer as a cause of premature death.document fetched 2026-09-27 02:45