Message from the Director of Research

We are proud to be one of the largest urologic research programs in the nation, with active basic science, translational and clinical research programs focused on prostate, bladder, kidney and pediatric urological diseases. 

The central theme of urologic cancer research is to improve the treatment outcomes of prostate and urothelial cancers through translational research. The long-term goal of the program is to reduce mortality for advanced prostate and urothelial cancers and improve outcomes for localized prostate and urothelial disease.

We direct our research interests at three highly interactive research themes, including:

• Investigate mechanisms of drug resistance to current therapies — This theme builds on our extensive research into castration-resistant prostate cancer (CRPC), chemoresistance in urothelial cancer and the translation of laboratory discoveries into clinical trials. We study androgen regulation in detail, focusing on aberrant androgen receptor (AR) activation by kinases, transcription factors, cytokines, intracrine androgens, microRNAs and coregulators.
• Identify molecular targets and develop therapeutic approaches — This theme stems from our research on resistance mechanisms and deep sequencing of biopsy specimens to identify druggable genetic targets. Using a patient-derived xenograft platform, we evaluate treatment efficacy, investigate resistance and translate findings into precision cancer medicine.
• Improve outcomes for localized cancers — This theme focuses on symptom self-management, treatment decision support, sexual recovery, social support and wellness among patients living with localized genitourinary cancers.

These themes use a translational approach that integrates preclinical models and clinical applications to develop mechanism-based treatments for prostate and urothelial cancers. The goal is to overcome resistance, optimize response and minimize toxicity. The department’s research programs foster collaboration and knowledge exchange with the prostate and urothelial cancer program at UC Davis Comprehensive Cancer Center.

In addition, we have an active cancer stem cell program focused on uncovering the mechanisms and biomarkers involved in cellular development. By studying the induction of human embryonic stem cells into specialized urothelial cells, we aim to advance bladder regeneration and gain critical insights into the origins of bladder cancer.

Our research team has made pioneering contributions to understanding and overcoming therapy resistance in advanced prostate cancer through discoveries that elucidate key mechanisms driving androgen receptor (AR) reactivation, metabolic adaptation and DNA damage repair. This work bridges fundamental biology and translational development, directly leading to multiple clinical trials and reshaping therapeutic strategies for castration-resistant prostate cancer.

A major focus of our research identified AKR1C3-mediated intracrine androgen synthesis as a major driver of resistance to enzalutamide and abiraterone. Our studies demonstrated that AKR1C3 upregulation restores AR signaling and that inhibition using NSAIDs or dual AR/AKR1C3 inhibitors (LX-1) re-sensitizes resistant tumors. Highlighted in Nature Reviews Urology (2015) and advanced to clinical trials (NCT02935205), this work established AKR1C3 as a clinically actionable target (Liu et al., Cancer Res. 2015; Ning et al., Cancer Res. 2024).

We also discovered that niclosamide, an anthelmintic drug, inhibits constitutively active AR splice variants such as AR-V7, restoring responsiveness to anti-androgens. This seminal finding (Clin Cancer Res. 2014) led to ongoing combination therapy trials (NCT02807805, NCT02532114). Our group further demonstrated that NF-κB2/p52 promotes AR-V7 expression and metabolic adaptation, identifying a key inflammatory-metabolic pathway in enzalutamide resistance (Nadiminty et al., Mol Cancer Ther. 2013, 2015).

Beyond hormonal resistance, our team revealed BCB1-mediated drug efflux as a critical mechanism of docetaxel resistance, showing that antiandrogens inhibit ABCB1 and reverse taxane cross-resistance (Clin Cancer Res. 2015; Mol Cancer Ther. 2017). Most recently, we defined mitochondrial metabolic reprogramming as a mechanism of PARP inhibitor (PARPi) resistance. Our group found that olaparib-resistant cells exhibit enhanced oxidative phosphorylation and upregulation of PINK1 and NDUFS4. Suppressing these regulators — genetically or via the novel molecule ARVib-7 — induces ferroptotic stress and restores PARPi sensitivity (Lombard et al., Mol Cancer Ther. 2022; Schaaf et al., Cancers 2023, Cancer Research Comm, 2024).