Please enable JavaScript or talk to your local administrator to get JavaScript enabled.

Project

Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma

Funder: National Cancer Institute

Funding period
USD 411 K
Funding amount
Abstract
Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma Bladder cancer is the ninth most common cancer worldwide and the fourth most common cancer in men. Despite intensive multi-modality therapy, approximately 50% of patients with muscle-invasive disease develop distant metastases and historically such patients had little hope of long-term survival. The development of immune checkpoint inhibitors is the most significant therapeutic advance in bladder cancer in three decades and the development of these agents have provided renewed hope to many patients with previously incurable metastatic disease. Anti-PD1/PD-L1 antibodies can induce durable complete responses in patients with metastatic bladder cancer with several immune checkpoint inhibitors are now FDA-approved for this indication. However, the majority of patients with metastatic urothelial cancers do not benefit from immune checkpoint blockade and some patients who initially respond later develop acquired resistance. The biologic basis for innate and acquired resistance to immune checkpoint blockade in urothelial cancer remains poorly defined. Urothelial cancers display a wide spectrum of variant morphologies that often co-exist within individual tumors. We have shown that this morphologic heterogeneity is often associated with intra-tumoral mutational heterogeneity. The current proposal is based upon preliminary data indicating that morphologic heterogeneity in bladder cancer is associated with genomic and immune heterogeneity and is predictive of a worse response to atezolizumab (an anti-PD-L1 inhibitor). Three aims are proposed. In Aim 1, we will perform integrated histologic, genomic and immune analyses of paired, macro-dissected, morphologically distinct areas from morphologically heterogeneous tumors from patients treated with immune checkpoint blockade to define the prevalence and extent of intratumoral genetic and immune heterogeneity. In Aim 2, these tissue profiling studies will be integrated with detailed clinical and patients response data to define the role of pre-existent histologic, genomic and immune heterogeneity in determining response to systemic immunotherapy. Finally, in Aim 3, we will study tumors collected at the time of disease progression in patients treated with immune checkpoint inhibitors to determine whether pre-existent drug resistant clones were present in morphologically heterogeneous primary tumors and that these less immunogenic cancer cells are a basis for drug resistance and disease progression in patients with morphologically heterogeneous tumors. The long-term translational objective will be to use the biologic insights gained to develop improved biomarkers of immunotherapy sensitivity and resistance, and to develop rational immune-based combination strategies that prevent or delay the emergence of drug resistant clones.
Similar projects All >
Sorted by: Start Date
Project list item
Recombinant CCL2 as a novel treatment strategy for bladder cancer

Bladder Cancer Advocacy Network to Neelam Mukherjee, Robert Scott Svatek

USD 50,000
2019 - 2020
Project list item
Targeting FGF in Bladder cancer after Neoadjuvant Immunotherapy and Surgery

American Association For Cancer Research to Joshua James Meeks

USD 25,000
2019 - 2020
Project list item
Identifying Immunological Basis for Bladder Cancer Sex Bias

Canadian Institutes of Health Research to Hyunwoo Kwon, Zihai Li

USD 26,219
2019 - 2022
Project list item
Refined phenotyping and personalized targeting of muscle-invasive bladder cancer

Swiss National Science Foundation to Roland Seiler, Vera Genitsch, Kiu Yan Charlotte Ng, Marianna Kruithof-de Julio, Franziska Singer

USD 702,564
2019 - 2023

System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • RCDC

    Human Genome

  • RCDC

    Cancer

  • RCDC

    Clinical Research

  • RCDC

    Genetics

  • RCDC

    Immunization

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • HRCS RAC

    5.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Clinical Medicine and Science