NOTCH signaling as a novel cancer therapeutic target.
NOTCH-ligand interaction is a highly conserved mechanism that regulates specific cell fate decision during development. In addition to its functions in developmental and cell maturation processes, studies indicate that NOTCH activation plays a role in the onset and progression of many human malignancies. The prevailing new strategy for rationally targeted cancer treatment is aimed at the development of target-selective "smart" drugs on the basis of characterized mechanisms of action. The connection between NOTCH signaling and tumorigenesis suggests that NOTCH may be such a target candidate. Gamma-secretase is a large membrane-integral multisubunit protease complex, which is essential for NOTCH receptor activation. Inhibitors of this enzyme are being developed for Alzheimer's disease, due to its role in cleaving beta-amyloid precursor in the brain. Recently, Gamma-secretase inhibitors (GSIs), as well as various biopharmaceutical or genetic NOTCH signaling inhibitors have been suggested as potential novel cancer therapeutic strategies. This review summarizes the evidence linking NOTCH signaling to several types of cancer, as well as the possible therapeutic indications of NOTCH inhibitors and the challenges facing their clinical development.
Miele
L
L
Cutaneous Oncology Program, Cardinal Bernardin Cancer Center and Departments of Pathology and Microbiology-Immunology, Loyola University Chicago, Maywood, IL 60153, USA.
Miao
H
H
Nickoloff
B J
BJ
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases; D002471:Cell Transformation, Neoplastic; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D016376:Oligonucleotides, Antisense; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human