Growth Factors in the Microenvironment

Growth factors are naturally occurring proteins that typically act as signaling molecules between cells and play a fundamental role in regulating a variety of normal cellular processes. Members of the TGFβ superfamily of growth factors, for example, can mediate diverse biological functions, including cell growth and differentiation, tissue homeostasis, immune modulation and extracellular matrix remodeling. Growth factors, including members of the TGFβ superfamily, such as myostatin, TGFβ1 and BMP6, have also been shown to play a fundamental role in a variety of disease processes, including neuromuscular disorders, cancer, fibrosis and anemia. Because of the importance of growth factors in multiple diseases, the pharmaceutical industry has made many attempts to inhibit growth factors in a variety of therapeutic settings.

However, traditional therapeutic approaches involve directly targeting an activated growth factor or its receptor systemically throughout the body and have suffered from a variety of shortcomings:

  • Multiple growth factors often signal through the same or overlapping sets of related receptors, making it difficult to specifically modulate one pathway over another
  • Members of the same growth factor superfamily share considerable similarities making it difficult to achieve selective inhibition of the targeted growth factor. Inhibiting both the intended growth factor target and other closely related targets can result in unintentionally broad systemic inhibition that can cause undesirable, and in many cases toxic, side effects
  • Systemic and nonselective inhibition of a growth factor can block the growth factor’s role in the disease process but can also simultaneously interfere with its normal physiological roles.

Our approach to the discovery and development of growth factor-targeted drugs is fundamentally new and different from traditional approaches. Our approach is based on the breakthrough discovery by the laboratory of our co-founder, Timothy A. Springer Ph.D. of Harvard Medical School and Boston Children’s Hospital, of the mechanism by which growth factors in the TGFβ superfamily are activated in the local microenvironment by a variety of specific stimuli in close proximity to the cell surface.

A Prime Example: Targeting of Transforming Growth Factor-Beta (TGFβ)

TGFβ1 is a growth factor that is first produced by cells in a precursor form known as a proform. The proform is processed by the cell into the mature growth factor and a propeptide. The cell then secretes a complex consisting of the mature growth factor in physical association with the propeptide. This complex is inactive or “latent,” and in 2011, the laboratory of Professor Timothy Springer at the Harvard Medical School and Boston Children’s Hospital discovered the structure of this complex and the molecular basis for how this inactive complex is activated.

TGFβ Activation and Inhibition

 

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