Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared with active surveillance in patients with low-risk prostate cancer. The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk prostate cancer tumors. Experimental Design: Transcriptome analysis of VTP-treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors. Results: Gene set enrichment analysis identifies the enrichment of androgen-responsive gene sets within hours after VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared with either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum prostate-specific antigen (PSA) confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining 7 days after treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. Conclusions: Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced prostate cancer. Clin Cancer Res; 24(10); 2408–16. ©2018 AACR.

With improved understanding of cancer biology and technical advancements in non-invasive management of urological malignancies, there is renewed interest in photodynamic therapy (PDT) as a means of focal cancer treatment. The application of PDT has also broadened as a result of development of better-tolerated and more effective photosensitizers. Vascular-targeted PDT (VTP) using padeliporfin, which is a water-soluble chlorophyll derivative, allows for tumor-specific cytotoxicity and has demonstrated efficacy in the management of urologic malignancies. Herein, we describe the evolution of photodynamic therapy in urologic oncology and the role of VTP in emerging treatment paradigms.

Molecular classification of upper tract urothelial carcinoma (UTUC) can provide insight into divergent clinical outcomes and provide a biological rationale for clinical decision-making. As such, we performed multi-omic analysis of UTUC tumors to identify molecular features associated with disease recurrence and response to immune checkpoint blockade (ICB). Targeted DNA and whole transcriptome RNA sequencing was performed on 100 UTUC tumors collected from patients undergoing nephroureterectomy. Consensus non-negative matrix factorization was used to identify molecular clusters associated with clinical outcomes. Gene set enrichment and immune deconvolution analyses were performed. Weighted gene co-expression network analysis was employed for unsupervised identification of gene networks in each cluster. Five molecular clusters with distinct clinical outcomes were identified. Favorable subtypes (C1 and C2) were characterized by a luminal-like signature and an immunologically depleted tumor microenvironment (TME). Subtype C3 was characterized by FGFR3 alterations and a higher tumor mutational burden, and included all tumors with microsatellite instability. Despite higher rates of recurrence and inferior survival, subtypes C4 and C5 harbored an immunologically rich TME favoring response to ICB. Limitations include extrapolation of molecular features of tumors from the primary site to determine response to systemic immunotherapy and the limited resolution of bulk sequencing to distinguish gene expression in the tumor, stroma, and immune compartments. RNA sequencing identified previously underappreciated UTUC molecular heterogeneity and suggests that UTUC patients at the highest risk of metastatic recurrence following surgery include those most likely to benefit from perioperative ICB.

The engraftment of human tumor tissues into immunodeficient host mice to generate patient-derived xenograft (PDX) models has become increasingly utilized for many types of cancers. By capturing the unique genomic and molecular properties of the parental tumor, PDX models enable analysis of patient-specific clinical responses. PDX models are an important platform to address the contribution of inter-tumoral heterogeneity to therapeutic sensitivity, tumor evolution, and the mechanisms of treatment resistance. With the increasingly important role played by targeted therapies in urological malignancies, the establishment of representative PDX models can contribute to improved facilitation and adoption of precision medicine. In this review of the evolving role of the PDX in urothelial cancer and kidney cancer, we discuss the essential elements of successful graft development, effective translational application, and future directions for clinical models.

Purpose: Vascular targeted photodynamic therapy (VTP) is a nonsurgical tumor ablation approach used to treat early-stage prostate cancer and may also be effective for upper tract urothelial cancer (UTUC) based on preclinical data. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model. Experimental design: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses. Results: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and prolonged survival to a greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells. Conclusions: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.

This review describes the current landscape of targeted therapies in urothelial carcinoma. The standard of care for advanced urothelial carcinoma patients remains platinum-based combination chemotherapy followed by immunotherapy. However, median overall survival for these patients is still <1 year and there is an urgent need for alternative therapies. The advent of next-generation sequencing has allowed widespread comprehensive molecular characterization of urothelial tumors and, subsequently, the development of therapies targeting specific molecular pathways implicated in carcinogenesis such as FGFR inhibition, Nectin-4, Trop-2, and HER2 targeting. As these therapies are demonstrated to be effective in the second-line setting, they will be advanced in the treatment paradigm to localized and even non-muscle invasive disease.