A View of the Notch Pathway
Aberrant Notch signaling can involve transcription factor CSL, coactivators (CoA), corepressors (CoR), MAML coactivator, and intracelluar domain (NICD).
A growing body of evidence suggests that aberrations in the Notch signaling pathway may contribute to the development of a variety of different human cancers, as well as potentially driving resistance to a number of targeted anticancer agents. Notch-targeted agents that were initially intended for the treatment of Alzheimer disease are now being examined for their possible anticancer activity. Toxicity issues have tempered success with the first generation of drugs, but a second generation is now waiting in the wings to enter clinical testing and may rejuvenate enthusiasm for this pathway.
What is the Notch signaling pathway?
In humans, the Notch pathway is composed of four known receptors (Notch 1-4), which span the cell membrane and are activated by the binding of one of two different families of ligands, named for their homology to the Drosophila genes: delta-like and jagged. Since the ligands are also bound to cell membranes, receptor activation typically occurs through direct contact between two cells, one expressing the receptor and one expressing the ligand.
Ligand binding causes the receptor to be broken down into several pieces through the action of two different enzyme families, the α-secretase complex (primarily A disintegrin and metalloproteinase 10 [ADAM10]) and the γ-secretase complex. This process frees up a portion of the receptor that is inside the cell membrane, known as Notch intracellular domain (NICD), which then travels into the nucleus where it activates a number of different genes involved in many important processes.
Notch signaling plays a vital role in communication between cells and in determining the “fate” of cells and ensuring they assume their proper role, both in adult tissues and during embryonic development. Though a relatively simple pathway at first glance, significant levels of complexity have been uncovered in recent years, with a variety of mechanisms in place that precisely control the timing, intensity, and biological consequences of Notch signaling.
Anticancer Therapy Potential Identified
As with other signaling pathways that control important cellular processes, when these pathways go awry it can often lead to the development of cancer. The first evidence of a role for Notch signaling in the development of cancer came in 1991 from patients with T-cell acute lymphoblastic leukemia; mutations in Notch1 later were observed in more than 50% of cases.
Although mutations in the component genes of the Notch signaling pathway are not always found to be directly causative of disease, they are often associated with poor prognosis and may define distinct clinical subtypes in a large number of different cancers. High levels of receptor or ligand expression have now been confirmed in pancreatic, breast, cervical, lung, and gastric cancers, among others, as well as in malignant gliomas and glioblastomas.
To add to the complexity of Notch signaling, researchers have discovered that while Notch pathway mutations have an oncogenic, tumor-promoting role in some cancers, they can have a tumor suppressive role in others, such as hepatocellular carcinoma and skin cancer. There is clearly still much to understand about the subtle nuances of Notch signaling in order to fully exploit therapies directed against it in as wide a range of cancers as possible.
Another reason for the interest in the Notch pathway is due to its role in determining the fate of stem cells. It is now widely accepted that there are populations of cancer stem cells (also dubbed tumorinitiating cells) within tumors that hold the key to their metastatic potential. Since Notch is involved in the maintenance of stem cells, drugs that target this pathway could help to eliminate cancer stem cells and prevent the recurrence of tumors that initially respond well to treatment.
Finally, the Notch signaling pathway has substantial crosstalk with other notorious signaling pathways that play a significant role in cancer, including the phosphatidylinositol-3-kinase (PI3K)/AKT pathway and the estrogen pathway. This is another driving factor behind the development of Notch-targeted cancer therapies, since combinatorial strategies could help to overcome resistance to other targeted drugs.
Disappointment Gives Way to Hope
The first Notch-targeting drugs to be developed were inhibitors of the enzyme γ-secretase in the 1990s, which work by blocking processing of the Notch receptor. The results of initial trials were disappointing, with gastrointestinal toxicities and diarrhea posing problems likely to limit dosing.
Human Notch1 (ligand binding region)
Merck’s MK-0752 and Roche’s RO4929097, are now showing promising signs of clinical activity in phase I/II clinical trials in patients with a range of different cancers and have been generally well tolerated. Experts are cautiously optimistic as optimal dosing and scheduling remains somewhat unclear. Furthermore, given the context-dependent action of components of the Notch pathway as both oncogenes and tumor suppressors, careful management of these and other drugs in development is needed in order to avoid additional cancer risks.