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Project

Development of Classifiers for Novel Bladder Cancer Subtypes

Funder: Congressionally Directed Medical Research Programs

Funding period
USD 707 K
Funding amount
Abstract
PUBLIC ABSTRACT

Muscle invasive bladder cancer (MIBC) is a heterogeneous disease with various responses to therapeutics. Current treatment options for MIBC are neoadjuvant cisplatin-based combination chemotherapy (NAC) followed by radical cystectomy or immunotherapy that were recently approved in the United States. However, there are no patient selection tools to predict who will benefit from chemotherapy, immunotherapy, or investigational drugs in bladder cancer. We and other investigators have identified molecular subtypes of MIBC, enriched with clinically actionable features such as specific mutations, copy number aberrations (CNAs), or molecular markers. Within our identified subtypes (MDA subtype), the p53-like subtype is characterized by fibroblast infiltration and chemo-resistance, while the luminal subtype includes papillary tumors enriched with activating FGFR3 mutations that may benefit from FGFR3 inhibitor treatment. The basal subtype is associated with the advanced stage and short survival in the absence of NAC – however, it showed the most survival benefit from NAC amongst all of the subtypes, despite the fact that the response rate to NAC in basal tumors still remains at only about 50%.



Our more recent analysis has identified two novel immune subtypes within basal MIBC – basal immune enriched (BIE) and basal immune suppressed (BIS) showing important clinical implications. The BIE subtype, featuring the enrichment of tumor infiltrating lymphocytes (TILs) and IFNg signature, had significantly improved survival outcomes with or without NAC, and a significant chemotherapeutic response rate (=pT1 at cystectomy; 80%, p<0.001). Conversely, the BIS subtype with a low TILs signature had the worst survival outcomes in the absence of NAC and demonstrated uncoupling of survival benefit and low pathologic response to chemotherapy (=pT1 at cystectomy; 24%, p<0.001). Interestingly, the pan-cancer predictive biomarker for immunotherapy was enriched in BIE subtype. Thus, in this study we propose to characterize our novel immune subtypes (BIE and BIS), define signaling pathways that are differentially activated between subtypes and are candidate therapeutic targets, and identify subtype-specific therapeutic strategies including chemotherapy and/or immunotherapy. We will also discover subtype-specific biomarkers with optimal number (£25 per each subtype) to develop cost-effective clinical assay.



Together, a multidisciplinary team of computational scientists and molecular biologists, and oncologists will leverage recent novel molecular subtypes of MIBC and utilize rigorous computational and statistical approaches to systematically characterize molecular subtypes and biomarkers and develop clinical assays. If successful, we will have systemic patient selection tools for therapeutic options in bladder cancer management.
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Cancer

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    4.1 Discovery and preclinical testing of markers and technologies

  • HRCS RAC

    5.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Clinical Medicine and Science