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Introduction
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July 1993 - present
January 1990 - July 1993
September 1986 - October 1989
Publications
Publications (546)
Introduction
Enfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related t...
Background: Sarcomatoid urothelial cancer of the bladder (SBC) is a rare, but aggressive histological subtype for which novel treatments are needed. Objective: We evaluated the clinical activity and safety of neoadjuvant cisplatin plus gemcitabine plus docetaxel (CGD) in muscle-invasive patients with SBC and assessed SBC tumor biology by whole tran...
Introduction: Interferon α gene therapy (Ad-IFNα/Syn3) is FDA approved for treatment of BCG-unresponsive non-muscle invasive bladder cancer. Ad-IFNα/Syn3 is a non-replicating adenovirus that when transduced into target tissues, produces IFNa2b protein with anti-tumor activity. In the phase 3 multicenter trial, 45.5% of patients with carcinoma-in-si...
Background and Objective: Determining novel biomarkers to identify patients that benefit and do not benefit from immune checkpoint inhibitor (ICI) therapy is critical to avoid overtreatment. Circulating tumor DNA (ctDNA) has emerged as a biomarker that associates with overall survival (OS) benefit to ICI in patients with muscle invasive urothelial...
Introduction: Enfortumab vedotin (EV), an antibody-drug conjugate targeting nectin-4, offers hope for urothelial carcinoma patients (UC) but prolonged use leads to treatment-related toxicities often necessitating dose adjustments. How EV engages nectin-4 at the tumor and its relevance to efficacy is unknown. To understand the pharmacodynamics (targ...
Bladder cancer is a histologically and clinically heterogenous disease. Most bladder cancers are urothelial carcinomas, which frequently develop distinct histological subtypes. Several urothelial carcinoma histological subtypes, such as micropapillary, plasmacytoid, small-cell carcinoma and sarcomatoid, show highly aggressive behaviour and pose uni...
mRNA‐based molecular subtypes have implications for bladder cancer prognosis and clinical benefit from certain therapies. Whether small extracellular vesicles (sEVs) can reflect bladder cancer molecular subtypes is unknown. We performed whole transcriptome RNA sequencing for formalin fixed paraffin embedded (FFPE) tumour tissues and sEVs separated...
Despite the introduction of several new agents for the treatment of bladder cancer (BC), intravesical BCG remains a first line agent for the management of non-muscle invasive bladder cancer. In this study we evaluated the antitumor efficacy in animal models of BC of a recombinant BCG known as BCG-disA-OE that releases the small molecule STING agoni...
Purpose:
The COXEN gene expression model with chemotherapy-specific scores (for DD-MVAC and GC) was developed to identify responders to NAC. We investigated RNA-based molecular subtypes as additional predictive biomarkers for NAC response, PFS, and OS in patients treated in S1314.
Experimental design:
237 patients were randomized between 4 cycle...
In an accompanying paper, Mattias Hoglund discusses on what is a bladder cancer molecular subtype. He emphasizes the need to consider the aim of tumor classification, which is obviously critical to the approach. He also focuses on considering primarily the identity features of the neoplastic cells. Here, we provide a counterpoint. While largely agr...
PURPOSE
There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus...
Bladder cancers (BCs) can be divided into 2 major subgroups displaying distinct clinical behaviors and mutational profiles: basal/squamous (BASQ) tumors that tend to be muscle invasive, and luminal/papillary (LP) tumors that are exophytic and tend to be non-invasive. Pparg is a likely driver of LP BC and has been suggested to act as a tumor suppres...
Background:
Although radical cystectomy (RC) is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC), many patients are ineligible for surgery or elect bladder preservation.
Objective:
To evaluate the efficacy and safety of atezolizumab in BCG-unresponsive high-ri...
Small cell/neuroendocrine bladder cancers (SCBCs) are rare and highly aggressive tumors that are associated with poor clinical outcomes. We discovered that lineage-specific transcription factors (ASCL1, NEUROD1, and POU2F3) defined three SCBC molecular subtypes that resemble well-characterized subtypes in small cell lung cancer. The subtypes expres...
Introduction: Developing optimized bladder cancer mouse models that can be used in the evaluation of immune based therapeutics remains a high priority in ongoing research.Experimental Procedures: In previous work by our collaborators, murine cell lines were generated that recapitulate the basal (BBN964, BBN966, and BBN975) molecular subtype of huma...
Enfortumab vedotin (EV) is an antibody-drug conjugate approved for the treatment of refractory advanced urothelial cancer. Cutaneous toxicity is well described but has not been correlated with response. In this retrospective single-center study, data from patients treated with more than one dose of EV between December 2017 and June 2022 were analyz...
Aims:
Small cell bladder carcinoma (SCBC) is a rare, divergent form of urothelial carcinoma (UC). We aimed to determine whether pure (n=16) and mixed (SCBC and UC; n=30) tumors differed in pathology, gene expression characteristics, genetic alterations, and clinical outcomes.
Methods and results:
Forty (87%) patients received first line chemothe...
Background:
Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients.
Objective:
To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam...
Purpose
To systematically review the literature to investigate racial disparities among bladder cancer clinical trial enrollees.
Methods
A systematic review was conducted using Ovid, MEDLINE® to identify clinical trials between 1970 and 2020. Articles were reviewed and were included if they assessed race in their outcomes reporting among bladder c...
Introduction: Intratumoral (IT) delivery of STING agonist ADU-S100 shows strong CD8+T cells-mediated antitumor immunity. However, rapid absorption from IT sites, short terminal half-life and adverse outcomes caused withdrawal of ADU-S100 from clinical trials. We reported development of BCG-STING, a preclinical candidate for non-muscle invasive blad...
Whole-organ mapping was used to study molecular changes in the evolution of bladder cancer from field effects. We identified more than 100 dysregulated pathways, involving immunity, differentiation, and transformation, as initiators of carcinogenesis. Dysregulation of interleukins signified the involvement of inflammation in the incipient phases of...
Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating Bacillus Calmette Guerin (BCG) unresponsive bladder cancer (BLCA). However, transient transgene expression and adenoviral immunogenicity may...
Background
We sought to determine whether differences in subtype distribution and differentially expressed genes exist between African Americans (AAs) and European Americans (EAs) in patients with high-risk nonmuscle-invasive bladder cancer (NMIBC).
Methods
We performed a retrospective cohort study including 26 patients (14 AAs and 12 EAs) from th...
536
Background: This trial evaluated COXEN, a gene expression model, as a predictive biomarker in muscle-invasive bladder cancer (BC) patients randomized to Gemcitabine-Cisplatin (GC) or dose-dense Methotrexate-Vinblastine-Adriamycin/doxorubicin-Cisplatin (ddMVAC). Primary results correlating COXEN with pathologic response at surgery have been repo...
527
Background: Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) have heterogeneous outcomes with African Americans (AAs) having worse survival than European Americans (EAs). It is unknown whether race-based biological differences contribute to this disparity. Methods: We performed a retrospective cohort study including patients f...
In addition to its role as a TB vaccine, BCG has been shown to elicit heterologous protection against many other pathogens including viruses through a process termed trained immunity. Despite its potential as a broadly protective vaccine, little has been done to determine if BCG-mediated trained immunity levels can be optimized. Here we re-engineer...
YAP1 is a principal component of the Hippo pathway and is considered as one of the critical regulators of tumorigenesis. Recent studies indicate that YAP1 can suppress the antitumor immunity and influence the differentiation of regulatory T cells (Tregs) by inducing TGFβ/SMAD pathway, but the mechanisms of YAP1 regulated modulation of tumor immune...
A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin–unresponsive non–muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A sta...
Bacillus Calmette-Guérin (BCG) is the most effective intravesical agent at reducing recurrence for patients with high-grade, non-muscle invasive bladder cancer. Nevertheless, response to BCG is variable and strategies to boost BCG efficacy have not materialized. Prior work demonstrated a requirement for either conventional αβ or non-conventional γδ...
B cells have been implicated as central regulators of immune responses in settings as diverse as mammalian pregnancy, mucosal tolerance, chronic infection states, autoimmunity, and the tumor microenvironment. Despite the established importance of B cells in these environments, the mechanisms by which B cells are maintained in these contexts remain...
Background
There is a great need to identify biomarkers that can accurately identify patients who will obtain the most clinical benefit from immune checkpoint inhibitor (ICI) therapy. While high intratumoral B cell gene expression correlated with an ICI response in melanoma, whether it adds predictive value in other cancers is unknown.
Objective
T...
Immunotherapy has revolutionized cancer treatment by improving survival in many cancer subtypes. While tumor infiltrating B (TIL-B) cells correlate with response to immunotherapy in selected solid tumors, they portend resistance to BRAF inhibitors in BRAF mutant melanoma. Thus, the mechanisms underlying TIL-B cell function within the tumor microenv...
p>Despite intensive efforts there is still a great need to identify biomarkers that can accurately identify patients who will obtain the most clinical benefit from immune checkpoint inhibitor (ICI) therapy. High intratumoral CD8+ T cell gene signature (CD8TGS) expression, tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1) expressi...
A comprehensive genomic characterization of a large, high-quality cohort of upper tract urothelial carcinomas (UTUCs) in this issue of Cancer Cell reveals that UTUCs can be divided into five DNA-based molecular subtypes. Feasibility data establish that molecular subtyping can be performed non-invasively by sequencing tumor DNA in urine.
Enfortumab vedotin (EV) was FDA approved in December 2019 for platinum- and checkpoint-refractory urothelial cancer based on an exceptional 44% response rate, and is currently approved for use after platinum and checkpoint inhibitor therapy. Enfortumab is an antibody-drug conjugate that targets Nectin-4, which is widely expressed in urothelial canc...
We used whole-organ mapping to study loco-geographic molecular changes in evolution of human bladder cancer from mucosal field effects. The integrative multi-platform analyses based on genome-wide RNA sequencing, methylation, copy number variations, and whole exome sequencing identified over 100 dysregulated canonical pathways involving immunity, t...
Background:
Current therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in osteosarcoma are incompletely understood. We investigated the tumor microenvironment of metastatic osteosarcoma with the goal of harnessing the immune system as a therapeutic strategy.
Methods:
66 osteos...
Bladder cancer (BC), a heterogeneous disease characterized by high recurrence rates, is diagnosed and monitored by cystoscopy. Accurate clinical staging based on biopsy remains a challenge, and additional, objective diagnostic tools are urgently needed. We used exosomal DNA (exoDNA) as an analyte, to examine the cancer-associated mutations and comp...
The antibody-drug conjugate enfortumab-vedotin acts by targeting nectin-4, a protein that is nearly ubiquitously expressed in conventional urothelial cancer. However, expression of nectin-4 in morphologic variants of urothelial carcinoma and nonurothelial histotypes was unknown. Immunohistochemistry for nectin-4 using was performed on 169 patients...
Purpose:
To compare upper-tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BUC) in same-patient metachronous-(m) and synchronous-(s) UTUC and BUC using next generation sequencing.
Materials and methods:
Consecutive untreated same-patient samples of UTUC and BUC were macrodissected from unstained formalin-fixed, paraffin-embedd...
Background
miRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer.
Methods
Taqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was...
Background
Although intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG’s antitumor effects. Here, we monitored...
Purpose:
Dose-dense Methotrexate-Vinblastine-Adriamycin-Cisplatin (ddMVAC) and Gemcitabine-Cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer (BC). The aim of this study was to validate the score from a Coexpression extrapolation (COXEN) algorithm-generated gene expression model (GEM) as a biomarker in patients und...
Background
The role of radiotherapy combined with immunotherapy in patients with non-muscle invasive bladder cancer (NMIBC) is currently being investigated. Radiation induced DNA damage triggering immunogenic tumor cell death and consequent immune responses in bladder tumor microenvironment is not fully understood. We compared local immune response...
Introduction
BCG remains first-line therapy for non-muscle invasive bladder cancer (NIMBC) but its mechanism of action is not fully understood nor is it completely efficacious. We engineered a recombinant BCG (rBCG) that releases increased levels of STING agonist, c-di-AMP and compared effects of rBCG to wild type BCG (WT-BCG) by assessing antitumo...
In 2014, there was a burst of studies on the molecular subtypes of bladder cancer in the published literature that was made possible by the advances in high-throughput technologies. Based on gene expression profiling, the major molecular classification subdivisions were basal and luminal subtypes, which resembled to those observed in breast cancers...
BACKGROUND: Bladder cancers have high total mutation burdens resulting in genomic diversity and intra- and inter-tumor heterogeneity that may impact the diversity of gene expression, biologic aggressiveness, and potentially response to therapy. To compare bladder cancers among patients, an organizational structure is necessary that describes the tu...
Background
Patients with relapsed metastatic osteosarcoma have no effective treatments available to them, ¹ and immunotherapy thus far has not succeeded in improving outcomes. 2–5 We aim to understand the immune architecture of the tumor microenvironment (TME) of osteosarcoma, with the goal of harnessing the immune system as a major therapeutic str...
Introduction
Small cell subtype is a rare and aggressive variant of bladder and upper tract cancers. Due to poor prognosis, patients with any component of this variant are often excluded from clinical trials, thus activity of novel agents in this population is unknown.
Patients and Methods
We retrospectively reviewed the Johns Hopkins Greenberg Bl...
Immunohistochemical stains have been suggested to aid in diagnostically challenging cases of urothelial carcinoma in-situ (CIS). Although full thickness immunostaining for CK20 is supportive of CIS, a subset of CIS cases is CK20(-), the clinical significance of which was unknown. This study included 43 patients with primary diagnosis of bladder CIS...
Bladder cancer is the most common cancer of the urinary tract. Although nonmuscle-invasive bladder cancers have a good prognosis, muscle-invasive bladder cancers promote metastases and have a poor prognosis. Comprehensive analyses using RNA sequence of clinical tumor samples in bladder cancer have been reported. These reports implicated the candida...
BCG is our most effective therapy for treating NMIBC, but over time, most patients will eventually recur. Alternative therapies to avoid cystectomy are needed as to date, only valrubicin, with a CR approaching 10% at 12 months in BCG-refractory CIS, has been FDA approved. Significant unmet need thus remains for an effective second-line therapy for...
Whole-transcriptome mRNA expression profiling studies have established that muscle-invasive bladder cancers (MIBCs) can be subdivided into “basal/squamous” and “luminal” molecular subtypes that are associated with distinct biologic and clinical properties. In general, basal/squamous tumors tend to be more highly enriched in canonical cancer stem ce...
Background: FGFR3 mutations (mutFGFR3) are present in up to 20-35% of metastatic bladder (mUC) and upper tract urothelial cancer, respectively. Early data suggest that these tumors respond better to FGFR inhibition as compared with immunotherapy.
Methods: Patients who failed prior treatment for mUC were treated with vofatamab, an antibody targeting...
Background: Standard of care for patients with muscle-invasive bladder cancer (MIBC) includes neoadjuvant cisplatin-based chemotherapy (NAC) followed by consolidative therapy with either chemoradiation or radical cystectomy (RC). Some patients experience robust pathologic responses to NAC, and these have been reported to associate with somatic muta...
Stage T1 bladder cancers have the highest progression and recurrence rates of all non–muscle-invasive bladder cancers (NMIBCs). Most T1 cancers are treated with bacillus Calmette-Guérin (BCG), but many will progress or recur, and some T1 patients will die from bladder cancer. Particularly aggressive tumors could be treated with early cystectomy. To...
Genomic profiling studies have demonstrated that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to frontline chemotherapy. We analyzed the mRNA expressions of signature luminal and basal genes in bladder cancer tumor samples from publicly available and MD...
We report a comprehensive molecular analysis of 34 cases of small cell carcinoma (SCC) and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 conventional UC bladder cancers used as the reference. SCCs showed mutational landscapes characterized by nearly uniform inactivation of TP53 and were dominated by Sanger mutation...
BCG remains first-line therapy for non-muscle invasive bladder cancer (NIMBC) but its mechanism of action is not fully understood nor is its efficacy complete. We engineered a recombinant BCG (BCG-STING) that releases increased levels the STING agonist, c-di-AMP. Compared with BCG, BCG-STING demonstrated superior antitumor efficacy in models of NMI...
Purpose:
Clinical trials with immune checkpoint (IC) inhibition in sarcomas have demonstrated minimal response. Here, we interrogated the tumor microenvironment (TME) of two contrasting soft tissue sarcomas (STS) - Rhabdomyosarcomas (RMS) and Undifferentiated Pleomorphic Sarcomas (UPS) - with differing genetic underpinnings and responses to IC inh...
Histological and molecular analyses of urothelial carcinoma often reveal intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels. Despite the clonal initiation of the tumour, progression and metastasis often arise from subclones that can develop naturally or during therapy, resulting in molecular alteration...
Little is known regarding the subclone evolution process in advanced bladder cancer, particularly with respect to the genomic alterations that lead to the development of metastatic lesions. In this project, we identify gene expression signatures associated with metastatic bladder cancer through mRNA expression profiling of RNA isolated from 33 prim...
Although predominantly urothelial, some bladder cancer and upper tract urothelial cancer (BC/UTUC) harbor histologic variants. Small cell BC (SCBC) variants comprised ˜5% of The Cancer Genome Atlas BC cohort, with a poor prognosis. We describe genomic profiles of BC/UTUC with small cell/neuroendocrine features identified in the Foundation Medicine...
Purpose:
To characterize immune cell expression among patients with Non-Muscle Invasive Bladder Cancer (NMIBC) treated with BCG.
Experimental design:
Patients with NMIBC treated with intravesical BCG (2008-2015) were identified, and a TMA was constructed using paired pre and post-BCG bladder samples. Immunohistochemistry was performed for CD8, C...
Background and Purpose
BCG unresponsive bladder cancer is an inherently resistant disease state for which the preferred treatment is radical cystectomy. To date, no effective intravesical therapies exist for patients who possess these resistant tumors. For this reason, many research groups are actively investigating/testing novel therapeutic agents...
Despite considerable advances in the management of urothelial carcinoma (UC), better risk stratification and enhanced detection of minimal residual disease are still urgent priorities to prolong survival while avoiding the morbidity of overtreatment. Circulating tumor cells and DNA (CTCs, ctDNA) are two biologically distinct “liquid biopsies” that...
Background:
Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application.
Objective:
To achieve an international consensus on MIBC molecular subtypes that reconciles the...
The three-dimensional cell culture system is an increasingly important technique for discovering new biological aspects of cancer cells. In the present study it was demonstrated that bladder cancer cell lines, RT4 and 5637, spontaneously formed round multicellular spheroids (MCSs) in suspension by the aggregation method. MCSs consisted of cells dif...
Bladder cancer is a heterogeneous disease. Interpatient heterogeneity in response to a drug limits treatment options and impairs improvement of patient survival. For example, approximately half of patients do not respond to cisplatin-based combination chemotherapy, although it is the standard of care for muscle-invasive and metastatic bladder cance...
Using gene expression profiling we previously reported the existence of 3 molecular subtypes (basal, p53-like and luminal) characterized by distinct gene expression patterns and clinical outcomes in muscle-invasive bladder cancer (MIBC). Among the subtypes, basal tumors were associated with advanced stage at presentation and shorter survival in the...
