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Project

Notch in bladder cancer: oncogene and tumour suppressor

Funder: Canadian Cancer Society

Funding period
CAD 996 K
USD 760 K
Funding amount
Abstract
Dr Peter Black and his team will be studying how the Notch signaling pathway drives bladder cancer growth, invasion and spread (metastasis) in laboratory models. Notch is a family of 4 different proteins that sit on the surface of the cell and normally control embryonic growth and development. In cancer, each one of these 4 Notch proteins can either be lost, indicating that it was a key brake in cancer growth (i.e. a tumour suppressor) or it can be overactive, indicating that it is driving the cancer growth (i.e. an oncogene). In bladder cancer, Notch-1 is a tumour suppressor. However, Dr Black will demonstrate in this project that Notch-2 is a key oncogene and targeting Notch-2 is a rational, novel treatment strategy. Bladder cancer is the 5th most common cancer, yet it remains understudied. Researchers are only now making strides in understanding the molecular make-up of this cancer. Recently, 3 different research groups have reported that Notch-1 is a tumour suppressor gene, whose loss is an important factor in driving the growth of some bladder cancers. Dr Black and his team have observed, however, that Notch-2 plays the opposite role. Patient bladder tumours frequently have too many copies of the Notch-2 gene and have increased levels of the Notch-2 protein, which correlates with worse survival. If researchers add Notch-2 to bladder cancer cells that do not have it, they cause them to grow more avidly. If they block Notch-2 levels in cells that have a lot of it, the cancer cells become less aggressive. Researchers can also treat human bladder tumours in mice with an antibody that specifically blocks Notch-2, and tumour growth is subsequently reduced. The role of Notch-2 in bladder cancer requires further study to establish its relevance as a driver of cancer growth and a target for new therapies. In addition, it is essential to determine how Notch-1 and Notch-2 can lead to such differing effects on cancer growth even though they have so many features in common. To address these objectives, Dr Black has 3 aims. In the first aim, researchers will create a mouse model that overexpresses Notch-2 specifically in the bladder and they expect this will cause bladder tumours to form. In the second aim, researchers will use advanced techniques to study the differences between Notch-1 and Notch-2 signaling that make these proteins have such different effects. They will especially investigate how each Notch protein controls the reading of genes in the cell nucleus. In the third aim, researchers will test an antibody that specifically blocks Notch-2 in different mouse models of bladder cancer, including tumours derived directly from patient cancer samples. Bladder cancer is the 5th most common cancer in Canada. Approximately half of patients with invasive bladder cancer will succumb to their disease, despite optimal therapy that may include chemotherapy and surgical removal of the bladder. While new targeted therapies are having significant impacts in other cancers, no relevant improvements have been achieved in bladder cancer therapy in the past 2 decades. Researchers have identified the Notch pathway in bladder cancer as a promising target for novel drugs and will demonstrate this definitively in this project. With completion of these studies, they anticipate being able to establish that Notch-2 is a target worthy of further testing in clinical trials involving patients with invasive bladder cancer. The ultimate goal is to control this often fatal disease, thereby alleviating patient suffering and improving survival.
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System

Categories
  • FOR (ANZSRC)

    0601 Biochemistry and Cell Biology

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • 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

    Basic Science