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Last Updated: 09/10/21

SPORE in Bladder Cancer

Memorial Sloan Kettering Cancer Center

Principal Investigator(s):

Dean Bajorin, MD
Dean Bajorin, MD

David Solit, MD
David Solit, MD

Principal Investigator(s) Contact Information

Dean Bajorin, MD
Attending Physician and Member
Frederick R. Adler Senior Faculty Chair
Memorial Sloan Kettering Cancer Center
1275 York Avenue
New York, NY 10065
(646) 888-4700

David Solit, MD
Attending Physician and Member
Geoffrey Beene Chair
Director, Marie-Josée and Henry R. Kravis Center for Molecular Oncology
Memorial Sloan Kettering Cancer Center
1275 York Avenue
New York, NY 10065
(646) 888-5435

Overview

Recent efforts to comprehensively define the landscape of genetic alterations in urothelial cancer (UC) and to understand their impact on drug sensitivity, as well as the exciting early results with immune targeting strategies suggest that prospective molecular profiling of blood and tumor tissue could improve the outcomes of urothelial cancer patients by personalizing care. This MSK SPORE in Bladder Cancer seeks to leverage recently initiated multicenter efforts to explore the molecular basis of inherited genetic susceptibility, exploit prospective molecular characterization to guide treatment, and to test the efficacy of immunotherapy-based combination approaches. This SPORE has the following translational research aims:

Aim 1. To develop predictive biomarkers of response and resistance to standard immunotherapies and chemotherapies, as well as investigational treatments. Specifically, we seek to build upon recent experimental and clinical breakthroughs, which have identified patterns of genomic instability associated with chemotherapy response, as well as immune and genomic signatures that correlate with response to immunotherapy to develop predictive biomarkers that can be used prospectively to guide treatment selection.

Aim 2. To identify and characterize germline genetic alterations that confer increased risk for the development of urothelial cancer. As germline alterations promote the development of tumors with genomic signatures that predict for sensitivity to particular chemotherapy or immunotherapy regimens, successful completion of this aim will not only facilitate the development of primary and secondary screening strategies but will also contribute to optimal selection of systemic therapy in individual patients with inherited cancer susceptibility.

Aim 3. To identify mechanisms of immunotherapy resistance and to develop more effective immunotherapies and combinatorial strategies to enhance response in patients with urothelial cancer. While checkpoint blockade represents the largest therapeutic advance in the treatment of metastatic urothelial cancer in decades, only a minority of patients respond. We seek to define mechanisms of resistance to both bacillus Calmette-Guérin (BCG) and immune checkpoint blockade with the goal of using these insights to develop more effective immunotherapies and as a guide to future combinatorial strategies.

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Project 1: Defining Predictors of Sensitivity to Cisplatin-Based Chemotherapy in Urothelial Carcinoma

Project Co-Leaders:
David B. Solit, MD (Basic Co-Leader)
Gopa Iyer, MD (Clinical Co-Leader)

Muscle-invasive bladder cancer (MIBC) is treated with cisplatin-based neoadjuvant chemotherapy (NAC) followed by complete removal of the bladder (radical cystectomy, RC), but some patients with cancer localized to the bladder may not require RC. Mutations in DNA damage response (DDR) genes predict response to cisplatin-based chemotherapy in MIBC, and some patients whose cancer is eliminated by NAC and refuse or are medically unfit for RC survive long-term with their bladders intact. This project will test whether patients with MIBC that carries DDR mutations can be successfully managed with NAC and transurethral resection of the bladder tumor through a prospective, multicenter clinical trial. In addition, whole exome sequencing will be performed to identify additional biomarkers of chemo-sensitivity. The project will also investigate the use of cell-free DNA from blood and urine as a platform for early identification of minimal residual disease and to explore tumor heterogeneity as a mechanism of drug resistance. If successful, the studies proposed could significantly expand the use of organ-sparing therapy for the curative-intent treatment of patients with MIBC. The prospective molecular characterization platform used in this project could also accelerate testing of novel immunotherapy or targeted approaches in patients unlikely to respond to cisplatin-based NAC.

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Project 2: Discovery and Characterization of Novel Genes and DNA Repair Pathways Predisposing to Urothelial Cancer

Project Co-Leaders:
Dean F. Bajorin, MD (Clinical Co-Leader)
Kenneth Offit, MD, MPH (Basic Co-Leader)
Vijai Joseph, PhD (Basic Co-Leader)
John Petrini, PhD (Basic Co-Leader)

Urothelial cancer has a substantial inherited component, with an estimated heritable fraction of ~30%. However, highly penetrant cancer susceptibility genes account for only a small fraction of genetic susceptibility to urothelial cancer. This project seeks to identify novel UC susceptibility genes by sequencing a collection of kindreds demonstrating familial UC derived from the MSK UC registry, international collaborators, and intramural NCI collaborators, as well as kindreds including cases of extreme phenotypes of early-onset disease (diagnosed at <= 45 years) and multiple primary tumors of which one is UC. Candidate susceptibility genes will be assessed by targeted deep resequencing of samples from multiple sources. High-value potential susceptibility genes will be functionally characterized by conducting studies in cellular systems. In sum, we hypothesize that, since the majority of the heritability for UC is yet undiscovered, there exist novel UC susceptibility genes that can be identified using WGS, WES, and gene-capture NGS in specifically ascertained kindreds (eg, extreme phenotypes such as early age of onset, multiple cases affected by UC, etc.).

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Project 3: Elucidating Mechanisms of Sensitivity and Resistance to Checkpoint Blockade Therapy for Rational Multi-Drug Immunotherapy in Urothelial Cancers

Project Co-Leaders:
Timothy A. Chan, MD, PhD (Basic Co-Leader)
Jonathan E. Rosenberg, MD (Clinical Co-Leader)

For patients with metastatic urothelial carcinoma whose disease has progressed despite first-line chemotherapy, treatment with immune checkpoint blockers is now a standard of care. However, response rates are low and reliable prognostic markers have yet to be identified. To identify predictive biomarkers of treatment response and resistance that could guide the rational development of more effective combination strategies, this project will systematically investigate the tumor and immune microenvironment of patients treated with immune checkpoint inhibitors (nivolumab, atezolizumab, pembrolizumab, durvalumab, or avelumab) utilizing blood, plasma, peripheral blood mononuclear cells, and tumor samples collected within the context of both therapeutic clinical trials and standard of care treatment. The cohort under study represents treatment with immunotherapy alone and in combination with other agents, across the full metastatic disease spectrum, in both treatment-naïve and treatment-resistant settings. This will allow cross-comparisons of checkpoint blockade inhibition alone and in combination with VEGF inhibition, CTLA-4 inhibition, standard cisplatin-based chemotherapy, TGF-beta inhibition, and antibody-drug conjugate therapy. The goal of these analyses is to develop more robust biomarkers of immunotherapy response, identify rational targets for effective combinatorial therapies, and understand acquired resistance to immune checkpoint blockade in patients with urothelial cancer.

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Project 4: Immunologic Predictors of BCG Immunotherapy for Bladder Cancer

Project Co-Leaders:
Michael S. Glickman, MD (Basic Co-Leader)
Gil Redelman-Sidi, MD (Basic Co-Leader)
Bernard H. Bochner, MD (Clinical Co-Leader)

The standard treatment for patients with high-grade non-muscle-invasive bladder cancer (NMIBC) is cystoscopic resection followed by intravesical bacillus Calmette-Guérin (BCG), which is the most effective/ least invasive therapy for that stage of bladder cancer. However, not all treated patients remain disease-free, and there are currently no reliable methods to predict an individual patient’s outcome. Our work shows that BCG acts by infecting cancer cells, leading to lysis and presentation of cancer antigens, which triggers a T-cell response that eliminates cancer cells. Thus, we will determine if BCG strains with enhanced infectivity, enhanced or impaired survival within cancer cells, or enhanced ability to induce an inflammatory response will improve the efficacy of BCG in a mouse model of bladder cancer. We will also determine the magnitude and diversity of the BCG-induced antitumor T-cell responses and test whether cancer neoantigen vaccination can enhance BCG-induced tumor elimination. Finally, we will use tumors from BCG-treated patients with NMIBC to determine whether neoantigen load and measures of the immune response directed against tumor neoantigens are predictive of therapeutic efficacy. In sum, this project will seek to develop a clinically useful tool to predict an individual patient’s likelihood of therapeutic response to BCG therapy and to identify strategies to enhance the efficacy of BCG therapy.

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Administrative Core

Core Directors:
Dean F. Bajorin, MD
David B. Solit, MD

The purpose of the Administrative Core is to support the translational research objectives of our SPORE in Bladder Cancer by serving as the organizational hub, optimizing collaboration among SPORE investigators within and outside the Memorial Sloan Kettering Cancer Center (MSK). The specific aims of the Administrative Core are (1) provide coordination for all educational and scientific activities of the SPORE, and (2) provide centralized administrative support of day-to-day activities to all the components of the SPORE: research projects, cores, and developmental research and career enhancement programs. The services centralized in the Administrative Core provide the following administrative and communications infrastructure that serve all components of the SPORE: financial management, grants administration, editorial services, coordination of the Developmental Research Program and Career Enhancement Program, meetings coordination, communication, and data management.

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Biostatistics and Bioinformatics Core

Core Directors:
Irina Ostrovnaya, PhD
Venkatraman Seshan, PhD

The role of the Biostatistics and Bioinformatics Core is to support the investigators of the SPORE in Bladder Cancer in their research efforts, including laboratory experiments, molecular studies and analysis of clinical trial and correlative data. Prior to the initiation of all studies, Core staff will consult with SPORE investigators to discuss the underlying scientific premise and translational goals of the project, to help the investigators select the most efficient and robust analytical methods, and to estimate sample sizes to ensure adequate power to address study objectives. In laboratory experiments, Core members will assist in the formulation of the experimental design and in the analysis and interpretation of the data at the conclusion of the study. For molecular studies using human tissues, Core members will work closely with the members of the Biospecimen Repository Core and will have primary responsibility for merging molecular and clinical data and for performing appropriate statistical and bioinformatics analyses. The members of the Biostatistics and Bioinformatics Core will also work with SPORE investigators to format data for publication and assist with deposition of genomic data into public repositories to facilitate validation of results by external investigators using their own analytical methods. For clinical studies, we will work with SPORE investigators to help set up effective systems to collect and track all required data. As studies proceed, Core staff will review project databases and monitor the quantity and quality of data collected, and we will suggest modifications to the design and analysis plans as appropriate. When studies are finished, the Core will conduct correct and efficient data analyses. We will also assist investigators with the preparation of any necessary graphs and tables, the interpretation of results, the preparation of presentations and manuscripts, and will consult on the design of subsequent research. If current statistical methodology does not adequately address a research question, alternative methodologies will be developed.

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Biospecimen Repository Core

Core Directors:
Hikmat A. Al-Ahmadie, MD
Victor E. Reuter, MD

The Biospecimen Repository Core is designed to provide support to the basic translational research efforts of the SPORE in Bladder Cancer. The Core will play a central role in collecting, annotating, storing, distributing, and tracking urothelial cancer biospecimens (tissue, urine, and blood) from patients enrolled in biospecimen banking and therapeutic research protocols. Detailed biospecimen annotation, including documentation of preanalytic processing variables, pathology findings, and patient clinical history information will be recorded in robust relational databases. We will conduct rigorous data quality assurance and quality control measures, and standardized longitudinal follow-up of all consented patients with materials in the urothelial cancer biospecimen repository. The Core will also provide SPORE investigators with expert histopathological evaluation of tumor samples both from patients enrolled on research protocols and from xenograft models. The Core will also provide assistance in performing and interpreting immunohistochemical and in situ hybridization assays, in selecting tissue for microdissection and construction of arrays. Given the significant morphologic heterogeneity of bladder cancers, these services require expertise beyond what MSK Pathology Core can provide, underscoring the importance of the role and input of the Core Directors. The specific aims of the core are:

Specific Aim 1. To maintain and expand a model urothelial cancer resource designed to collect, annotate, store, process, and distribute biospecimens for translational urothelial cancer research.

Specific Aim 2. To perform systematic pathologic evaluation of all human and animal biospecimens and preparation of appropriate biospecimens for use by SPORE investigators.

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Developmental Research Program

Program Directors:
David B. Solit, MD
Luis A. Diaz, Jr., MD

The goal of the Developmental Research Program is to support innovative translational research projects in urothelial cancer by establishing mechanisms for rapid funding. Developmental Research Program funds in the SPORE in Bladder Cancer, supplemented by institutional funds, will allow us to support projects by new and established investigators that are critical to the generation of new ideas in the prevention, diagnosis, and treatment of urothelial cancer. We will request proposals for urothelial cancer pilot projects with translational potential from clinical and basic investigators within the larger MSK community, including Rockefeller University and Weill Cornell Medical College. After rigorous peer review by the DRP Directors, Internal and External Advisory Boards, and the Patient Advocate, the most promising new projects from this wide portfolio of developmental research projects will be selected. Preference will be given to projects that complement the long-term research goals of the SPORE and advance our translational research objectives. The DRP may also solicit and fund experimental or clinical initiatives that address an urgent and specific need in the MSK SPORE in Bladder Cancer program or a unique research opportunity.

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Career Enhancement Program

Program Directors:
Dean F. Bajorin, MD
Mark G. Kris, MD

The Career Enhancement Program (CEP) will prepare the most promising and motivated young clinician-scientists for independent careers as investigators in translational research in urothelial cancer. Eligible candidates will include junior faculty with a demonstrated interest in urothelial cancer research, advanced postdoctoral clinical fellows who exhibit outstanding research potential in urothelial cancer and are ready to transition to a faculty position within 1 year, and established investigators who wish to enhance or refocus their careers on translational research in urothelial cancer. We have designed the CEP to form both an interdepartmental and an inter-institutional training ground in which to nurture 2 talented new investigators each year—from either basic research or clinical backgrounds—committed to translating new scientific developments in urothelial cancer research into clinically relevant therapeutic strategies. By combining the research and academic resources available throughout MSK and at our affiliated institutions, CEP recipients will benefit from the intersection of a comprehensive educational program, career enrichment activities, and a rich research environment cultivated by the senior investigators in the SPORE in Bladder Cancer. The diverse research areas in our proposed SPORE in Bladder Cancer pursue research questions at every stage of the disease.

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