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Project

Investigating the effect of ERCC2 mutations on DNA repair capacity and chemo-radiotherapy response in muscle-invasive bladder cancer

Funder: Burroughs Wellcome Fund

Funding period
USD 700 K
Funding amount
Abstract
Lay Abstract
An estimated 75,000 new cases of bladder cancer will be diagnosed in the US in 2016, making it the fifth most common cancer among US adults. Although the majority of bladder cancers are diagnosed at an early stage when tumor removal alone is curative, approximately one in four patients presents with muscle-invasive disease. Despite aggressive multimodality therapy, the 5-year survival rate for patients with muscle-invasive bladder cancer (MIBC) is only 50% and has improved little in the past 30 years.



Historically, the treatment for MIBC patients in the US has involved cisplatin-based chemotherapy followed by removal of the bladder (cystectomy). Despite recent advances in developing molecularly-targeted agents, chemotherapies such as cisplatin -- which work by damaging tumor cell DNA -- remain the backbone of treatment for MIBC and many other tumor types. However, there is significant variability in tumor response to cisplatin-based therapy among MIBC patients, and identifying predictive biomarkers of response to cisplatin and other DNA-damaging chemotherapies represents a critical unmet need in clinical oncology.



In an effort to identify genetic determinants of cisplatin response in MIBC, our group recently performed a DNA sequencing analysis of MIBC cisplatin responders and non-responders. We identified an enrichment of mutations in the gene ERCC2 in tumors from responders compared to non-responders. ERCC2 is a member of the nucleotide excision repair (NER) pathway that is responsible for repairing cisplatin-mediated DNA damage. Therefore, we hypothesized that ERCC2 mutations confer tumor cisplatin sensitivity by preventing NER-mediated repair of cellular cisplatin damage.



We now aim to further characterize the relationship among ERCC2 mutations, cellular DNA repair capacity, and treatment response in MIBC. In our first aim, we will use a novel high-throughput assay developed in our laboratory to interrogate the effect of each of the ERCC2 mutations identified across several large clinical cohorts. We will correlate functional data from our assay with available clinical tumor response and patient outcome data in order to define the clinically relevant landscape of ERCC2 mutations across MIBC. We believe this effort will also lead to a deeper understanding of ERCC2 biology and will allow us to predict the functional effects of novel ERCC2 mutations identified in future studies. Finally, we will adapt our assay for use on fresh MIBC biopsies with the goal of developing a clinical assay that will provide a real-time readout of DNA repair capacity in tumor cells.



In our second aim, we will use genetic and cellular approaches to carefully dissect the role of ERCC2 mutations in MIBC biology. We will first probe the molecular mechanisms by which ERCC2 mutations confer cisplatin sensitivity and will test the effect of ERCC2 mutations on cellular sensitivity to established and emerging MIBC therapies, including immunotherapy agents. In order to study the effect of ERCC2 mutations on tumor formation, we will introduce an ERCC2 mutation in a normal human bladder cell line and will measure the effect on cellular properties. We hypothesize that ERCC2 mutations contribute to the tumor formation and confer a unique set of cellular properties and sensitivities.



In our third aim, we will investigate the association of ERCC2 mutations with treatment response and survival outcomes among MIBC patients treated using concurrent cisplatin-based chemotherapy and radiation (CRT). CRT is an alternative approach to cystectomy-based treatment and provides patients an opportunity to preserve their bladder. We will perform targeted sequencing of ERCC2 and 1000 additional cancer genes in two large MIBC cohorts treated using CRT. We hypothesize that ERCC2 mutations are associated with improved response to CRT and may therefore represent a useful biomarker to identify patients who are ideal candidates for a bladder-sparing treatment approach.
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System

Categories
  • FOR (ANZSRC)

    0604 Genetics

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • HRCS RAC

    4.1 Discovery and preclinical testing of markers and technologies

  • HRCS RAC

    4.2 Evaluation of markers and technologies

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Clinical Medicine and Science