Table 2.

Benefits and drawbacks of different strategies for Notch inhibition in cancer

	Benefits	Drawbacks
Gamma-secretase inhibitors	Effective Notch inhibitors in most settings. Oral agents Already in clinical trials Numerous GSIs already developed or in the pipeline	Nonspecific. GI toxicity.
Alpha-secretase inhibitors	May be active outside the cell, so not vulnerable to efflux pumps. Oral agents.	Nonspecific. Likely GI toxicity.
Small-molecule blockers	Potential for oral bioavailability and for specificity for individual Notch family members or ligands.	Purely theoretical at this stage.
Endosomal acidification inhibitors	Includes known agents, which may include some already tested in humans. May be oral.	May be highly nonspecific and be similar to GSIs.
Blocking or NRR (negative regulatory region) antibodies	Can be specific for individual Notch family members or Notch ligands. Targeting of individual Notch family members may minimize side effects such as GI toxicity.	Difficult access—may be most useful intravascularly or with local delivery. Large molecule.
Stapled peptide	Highly specific for the Notch pathway. Relatively small molecule.	Difficult access to cells—may be most useful intravascularly or with local delivery.
Delivery of notch-inhibiting genes	May be quite specific.	Difficult access, likely requiring viral or liposomal delivery. Probably inefficient.
Delivery of siRNAs, shRNAs, or microRNAs	siRNAs/shRNAs can be very potent Notch inhibitors. MicroRNAs are found endogenously and are likely tolerated well by normal cells.	Difficult access, likely requiring viral or liposomal delivery. Likely inefficient but efficiency may be boosted by transduced cells shedding microvesicles taken up by nearby cells.