Targeting notch signaling pathway in cancer: clinical development advances and challenges.
Notch signaling plays an important role in development and cell fate determination, and it is deregulated in human hematologic malignancies and solid tumors. This review includes a brief introduction of the relevant pathophysiology of Notch signaling pathway and primarily focuses on the clinical development of promising agents that either obstruct Notch receptor cleavages such as γ-secretase inhibitors (GSIs) or interfere with the Notch ligand-receptor interaction by monoclonal antibodies (mAbs). Antitumor activity by GSIs and mAbs administered as single agent in early phases of clinical trials has been observed in advanced or metastatic thyroid cancer, non-small cell lung cancer, intracranial tumors, sarcoma or desmoid tumors, colorectal cancer with neuroendocrine features, melanoma and ovarian cancer. A number of mechanism-based adverse events particularly gastrointestinal toxicities emerged and mitigation strategies are developed after testing multiple GSIs and Notch targeting mAbs. We also discuss pharmacodynamic biomarkers in conjunction with methods of assessment of the molecular target inhibition validation. Biomarkers of efficacy or benefit may be of importance for a successful development of this class of drugs.
Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, United States. Electronic address: takeben@mail.nih.gov.
Naoko
N
Takebe
National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, United States.
Dat
D
Nguyen
National Clinical Target Validation Laboratory, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, United States. Electronic address: Sherry.Yang@nih.gov.
Sherry X
SX
Yang
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D009389:Neovascularization, Pathologic; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D015415:Biomarkers; D051880:Receptors, Notch
ADAM; Biomarkers; CR; CSCs; Clinical trials; DLL; DLT; Delta-like ligand; Diarrhea; EDTA; GBM; GSI; JAG; Jagged; MAML; MSFE; MTD; Monoclonal antibodies (mAbs); NICD; NSCLC; Notch intracellular domain; Notch signaling; PD; PK; PR; RECIST; SD; T-ALL; T-LL; T-cell acute lymphoblastic leukemia; T-cell lymphoblastic lymphoma; TACE; TICs; a disintegrin and metalloproteases; cancer stem cells; complete response; dose limiting toxicity; ethylenediaminetetraacetic acid; glioblastoma multiforme; mAb; mammosphere-forming efficiency; mastermind-like; maximum tolerated dose; metalloproteinase tumor necrosis factor-α-converting enzyme; monoclonal antibody; non-small cell lung cancer; partial response; pharmacodynamics; pharmacokinetics; response evaluation criteria in solid tumors; stable disease; tumor initiating cells; γ-Secretase inhibitors; γ-secretase inhibitor