Targeting Notch signaling pathway in cancer: Clinical development advances and challenges

Abstract

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.

Hes1: a key role in stemness, metastasis and multidrug resistance

“…For instance, when treated with anti-hedgehog and anti-Notch compounds in vitro, glioma cells show apoptosis phenotype, CSCs depletion and sensitivity to temozolomide. 90,93 As discussed earlier, the third cleavage mediated by g-secretase is a crucial step for Notch activation and is targeted by GSI inhibitors which have been evaluated in phase 1 clinical trials, such as MK-0752, PF-03084014, RO-4929097, reviewed by Takebe N. 94 With the rigorous estimation in preclinical models, it is safe to say that GSI inhibitors do show its anti-proliferation, anti-CSC and pro-apoptotic effects on tumor. However, GSI inhibits Notch target genes without selection which causes a rapid differentiation of intestinal progenitor cells into goblet cells.…”

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

“…Promising strategies targeting individual Notch receptors, ligand-receptor interactions, and Notch transcriptional activity have been developed and have demonstrated anticancer activity in animal models (52)(53)(54). Humanized monoclonal antibodies that block the ligand-receptor interaction between Notch and its ligand DLL4 demonstrate potent anticancer activity in patient-derived xenograft models (52).…”

“…Humanized monoclonal antibodies that block the ligand-receptor interaction between Notch and its ligand DLL4 demonstrate potent anticancer activity in patient-derived xenograft models (52). Another class of antibodies that targets individual Notch receptors, locking them in an inactive conformation, has also demonstrated promising therapeutic potential (53). Another strategy to inhibit Notch receptors is the use of GSIs that block regulated intramembrane proteolysis and subsequent Notch receptor activation (55).…”

Cancer stem-like cells and thyroid cancer

“…However, the CSCs in the tumor are resistant to conventional therapy such as surgery and radioactive iodine treatment (Sipos & Mazzaferri 2010) and the patient usually has a relapse with re-growth of the cancer, including the CSCs. CSC-specific therapy such as drugs targeting the Notch pathway (Takebe et al 2014) or the evaluation of MEK and JNK pathway inhibitors as therapeutic agents (Balko et al 2013) needs to be developed, which would lead to the elimination of the CSCs. If this therapy is combined with conventional therapy it may be possible to eradicate even highly lethal cancers such as anaplastic thyroid carcinomas.…”