Future Perspectives: Therapeutic Targeting of Notch Signalling May Become a Strategy in Patients Receiving Stem Cell Transplantation for Hematologic Malignancies

Table 3

Potential molecular tools for targeting of Notch signalling.

Molecular tool	Observations in clinical or experimental studies	References
Natural receptor ligands
JAG2-expressing hematopoietic progenitor cells	Activation of Notch3 signalling with increased Treg proliferation and prevention of diabetes in NOD mice.	[63]
Fusion proteins of natural ligands and Fc-Ig	DLL1-IgG-Fc has been used for expansion of human umbilical cord stem cell expansion; cells caused no unexpected toxicity and contributed to long-term engraftment. Could be used for transplantation.	[116]
JAG1- and DLL2-Fc fusion proteins	Both types of fusion proteins have shown immunomodulatory effects in experimental murine disease models.	[8, 68]
Receptor- or ligand-directed antibodies
Agonistic antibodies	Agonistic antibodies have been identified for their reactivity against Notch2 or Notch3.	[117, 118]
Antagonistic antibodies directed against Notch	Several antagonistic Notch1-, Notch2- or Notch3-directed antibodies have been tested in vitro and in vivo.	[8, 58, 117, 119, 120]
Antagonistic antibodies directed against Notch ligands	Both DLL- and JAG1- specific antibodies show immunomodulatory effects in murine disease models.	[8, 68]
DLL1 neutralizing antibodies	Reduced Th1 responses and improvement of EAE symptoms.	[8, 68]
DLL4 neutralizing antibodies	In CSC-driven colon and breast xenograft models, anti-human DLL4-blocking antibodies inhibited tumour growth and reduced tumour-initiating cell frequencies.	[121]
Antibodies that inhibit the transcription-regulating complex	Development of such antibodies could inhibit parts of the Notch-initiating effects and possibly limit the toxicity.	[122]
Activating JAG1-Fc fusion protein	Improvement of EAE symptoms.	[8, 68]
Activating DLL2-Fc fusion protein	Increased Th1 responses and progression of EAE symptoms.	[8, 68]
Inhibition of intracellular signalling
γ-secretase inhibitor	Reduced Notch1 signalling and FoxP3 expression in Treg cells in murine disease models.	[58, 61, 67]
Proteasome inhibitors	Inhibition of noncanonical Notch signalling.	[2, 10, 123, 124]
Inhibition of the PI3K-Akt-mTOR pathway	Inhibition of noncanonical Notch signalling.	[2, 10, 48]
Peptide that inhibits assembly of the transcription-regulating complex	The small hydrocarbond-staple peptide SAHM1 inhibits Notch signalling in vitro.	[122]

Abbreviations: Experimental autoimmune encephalomyelitis (EAE), Delta-like (DLL), Jagged (JAG), Helper T cells (Th), Cancer stem cell (CSC).