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A New Mechanism for Inhibiting BCL9 in a Poor Prognosis Subtype of Colorectal Cancer

New inhibitors targeting the adrenergic receptor are a new treatment for colorectal cancer characterized by high stromal cell infiltration and BCL9 localization in paraspeckles.

  • Therapeutics

Project Overview

  • B-cell lymphoma 9 (BCL9), an oncogene that is typically known for its role as a transcriptional co-activator of β-catenin in the canonical Wnt signaling pathway, plays a crucial role in the pathogenesis of colorectal cancer.
  • However, attempts to inhibit BCL9 via the β-catenin/Wnt signaling pathway have been largely unsuccessful.
  • Dana-Farber scientists have invented a new strategy for inhibiting BCL9 providing alternative methods and compositions for treating this disease. 
  • The technology is available for licensing or for sponsored research or collaboration.

Technology

BCL9 is known to promote CRC by enhancing cell proliferation and remodeling the tumor microenvironment, particularly by influencing processes that can improve communication among tumor cells. This new invention addresses the need to further characterize the role of BCL9 in CRC pathogenesis. BCL9 can also promote gene expression changes that are associated with a poor prognosis in CRC.

A research team from the Dana-Farber Cancer Institute discovered a novel, β-catenin-independent function of BCL9 involving previously unknown interactions between BCL9 and paraspeckle proteins that improve communication among tumor cells and with cells in the tumor microenvironment. This interaction leads to tumor microenvironment remodeling and CRC progression by enhancing neural-like, multicellular communication properties among the tumor cells, including neurotransmitter release.

A poor prognosis subtype of CRC, named C1, was identified wherein BCL9 expression and its localization into paraspeckles can determine patient survival time. Accordingly, the invention is directed to the characterization of the C1 subtype in patients based on:

  • expression levels of specific genes associated with wound healing, tissue remodeling, or neuron projection
  • levels of stromal cell infiltration
  • BCL9 nuclear staining patterns in tumor cells relative to stromal cells. This confirms a previously unrecognized role for BCL9 in CRC progression, providing novel approaches for diagnostic and therapeutic intervention. 

Further Details:

Team Members: Ruben Carrasco, MD, PhD, Meng Jiang, MD

Applications

Therapeutic interventions for CRC involving inhibition of BCL9 function or blockade of neurotransmitter receptors or calcium channels with FDA-approved drugs commonly used to treat hypertension and heart disorders (e.g., beta-blockers). 

Opportunities

Dana-Farber is seeking Sponsored Research, Collaboration, and/or Licensing opportunities for this technology. 

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Team Members