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Project

Proteogenomic characterization of muscle invasive bladder cancer to identify mechanisms of resistance and targets for therapy

Funder: Bladder Cancer Advocacy Network

Funding period
USD 300 K
Funding amount
Abstract
Cisplatin-based neoadjuvant chemotherapy (NAC) is a standard of care for patients with non-metastatic muscle invasive urothelial bladder cancer, yet only one quarter of patients may be treated and derive a benefit with current standard of care therapy. Clinical trials are designed to validate predictive biomarkers associated with response while current treatments remain “one size fits all”. Patients with residual muscle invasive cancer following NAC have poor outcomes and there is no standard of care for these patients. Insights into mechanisms of resistance to NAC suggest that DNA damage repair plays an important role and our recent study suggests an important role for prostaglandin E2 to promote expansion of resistant cancer stem cells. Intrinsic molecular subtypes provide insights into potential mechanisms of resistance and a genomic roadmap that may help identify patients who may or may not respond to NAC. While TCGA estimates that up to 2/3 of patient may have one or more actionable mutations, biomarker/target validation is just underway. Proteins are the end effectors of genomic alterations and there is a knowledge gap in our understanding of how genomic changes in cancer drive the proteome and phosphoproteome to execute phenotypic characteristics. To provide greater analytical breadth, the NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) is using mass spectrometry to analyze the proteomes of genome-annotated TCGA tumor samples but has not prioritized bladder cancer. Our goal in this proposal is to integrate analysis of proteomics and genomics of primary muscle invasive bladder cancer and pre-clinical PDXs and canine naturally occurring bladder cancer in order to provide additional insights into mechanisms of chemotherapy resistance and identify and prioritize candidate driver genes and targeted therapies for a more rational approach to personalized therapy and expand the patient population that can be treated effectively with systemic therapy.
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • RCDC

    Human Genome

  • RCDC

    Cancer

  • RCDC

    Clinical Research

  • RCDC

    Genetics

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Clinical Medicine and Science