Funded Projects
R01CA311048 (May 2026-April 2031): Dissecting mechanism of EPHX2 deficient Bladder Cancer and targeting metabolic and immunologic vulnerabilities
Bladder cancer is molecularly heterogeneous, yet treatment remains largely uniform. Our studies identified frequent loss of EPHX2, a tumor-suppressive metabolic enzyme, in bladder cancer and demonstrated that EPHX2 deficiency promotes EET accumulation, AKT–PKN3 signaling, NECTIN4 expression, and tumor progression. EPHX2-deficient tumors also exhibit enhanced immune signaling. This project will define the metabolic and immune mechanisms driven by EPHX2 loss and evaluate PKN3 inhibition, NECTIN4-targeted therapy, and immune checkpoint blockade as biomarker-driven therapeutic strategies for EPHX2-deficient bladder cancer.
R01CA282282 (July-2023- June-2028): Decoding tumor metabolic and immunologic interactions driving different biological subtypes in patients with bladder cancer.
Bladder cancer comprises distinct biological subtypes with variable clinical outcomes. Our studies identified mitochondrial complex I–GLS1–dependent metabolism as a key driver of aggressive bladder cancer and revealed its interaction with immune signaling. This project will define the metabolic and immunologic mechanisms underlying these subtypes using metabolomics, single-cell RNA sequencing, and imaging mass cytometry, and evaluate complex I and GLS1 inhibition, alone or with immunotherapy, as biomarker-driven therapeutic strategies.
U01CA214263 (Sen, June 2024-July-2029) Circulating Biomarkers and Imaging for Early Detection of Pancreatic Cancer (Sub award with Putluri; BCM)
The overall goal of this project is to validate biomarker signatures associated with aberrantly expressing pathways in pancreatic cancer for early-stage PDAC detection among asymptomatic patients with high-risk clinical, genetic and/or familial susceptibility characteristics. PDAC early detection signatures, developed with circulating transcriptomics, proteomics and metabolomics biomarkers identified in the first funding cycle, will be characterized for their association with heterogeneous disease subtypes and integrated with imaging-based disease subtype features derived with machine learning methods from CT/MRI scans reflecting functional changes in malignant lesions of the pancreas
R37CA289419 (Ripley; Mar 2024-Feb 2029) Targeting the Mitochondria to Overcome Resistance to Immune Checkpoint Inhibition in Malignant Pleural Mesothelioma (Sub award with Putluri; BCM)
Malignant pleural mesothelioma (MPM) is an asbestos-related cancer with poor survival and limited treatment options. Although immune checkpoint inhibitors (ICIs) have improved outcomes, only a subset of patients respond, highlighting the need for strategies to overcome therapeutic resistance. Our studies identified the mitochondrial protein Mcl-1 as a key mediator of tumor cell survival and found increased mitochondrial methionine metabolism and PRMT5 activity following ICI treatment. We hypothesize that targeting PRMT5 or Mcl-1 will restore tumor sensitivity to therapy and enhance ICI efficacy. This study will define these mechanisms and provide a translational foundation for rapidly advancing effective combination therapies into clinical trials to improve survival in patients with MPM.