Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model

Arcaroli, John J.; Quackenbush, Kevin S.; Purkey, Alicia; Powell, Rebecca W.; Pitts, Todd M.; Bagby, Stacey M.; Tan, Aik Choon; Cross, Benjamin; McPhillips, Kelly L.; Song, Eun Kee; Tai, Wai Meng David; Winn, Robert A.; Bikkavilli, Kamesh; Scoyk, Michelle Van; Eckhardt, S. Gail; Messersmith, Wells A.

doi:10.1038/bjc.2013.361

Cited by 37 publications

(37 citation statements)

References 31 publications

(41 reference statements)

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“…75,179 These findings suggest that Notch inhibitors, including GSIs, could block β-catenin mediated tumorigenesis, and vice versa. Interestingly, preclinical data shows that PF-03084014-responsive tumours have elevated baseline expression levels of Notch and Wnt pathway genes, 180 supporting the importance of crosstalk between these pathways in tumorigenesis. Furthermore, PF-03084014 inhibited both Notch and Wnt pathways, resulting in a reduction in tumour growth in a CRC xenograft model.…”

Section: Crosstalk Between Signalling Pathwaysmentioning

confidence: 94%

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

et al. 2015

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During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents.

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Section: Crosstalk Between Signalling Pathwaysmentioning

confidence: 94%

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

et al. 2015

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“…Erlotinib was a generous gift from Dr. William Pao at Vanderbilt University. Gamma secretase inhibitor (PF-03084014) was kindly provided by Pfizer Global Research and Development, La Jolla Laboratories (San Diego, CA) and was described previously(23, 24). …”

Section: Methodsmentioning

confidence: 99%

EGFR Blockade Enriches for Lung Cancer Stem–like Cells through Notch3-Dependent Signaling

et al. 2014

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Mutations in the epidermal growth factor receptor (EGFR) are the most common actionable genetic abnormalities yet discovered in lung cancer. However, targeting these mutations with kinase inhibitors is not curative in advanced disease and has yet to demonstrate an impact on potentially curable, early-stage disease, with some data suggesting adverse outcomes. Here, we report that treatment of EGFR-mutated lung cancer cell lines with erlotinib, while showing robust cell death, enriches the ALDH+ stem-like cells through EGFR-dependent activation of Notch3. Additionally, we demonstrate that erlotinib treatment increases the clonogenicity of lung cancer cells in a sphere-forming assay, suggesting increased stem-like cell potential. We demonstrate that inhibition of EGFR kinase activity leads to activation of Notch transcriptional targets in a gamma secretase inhibitor sensitive manner and causes Notch activation. leading to an increase in ALDH high+ cells. We also find a kinase-dependent physical association between the Notch3 and EGFR receptors and tyrosine phosphorylation of Notch3. This could explain the worsened survival observed in some studies of erlotinib treatment at early-stage disease, and suggests that specific dual targeting might overcome this adverse effect.

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“…PF-03084014 (PF-4014) is a GSI developed by Pfizer, which shows antitumor efficacy in hematologic, breast, colorectal, and pancreatic cancer models (13)(14)(15)(16)(17)(18), and suppresses hepatic metastases of neuroblastoma and breast cancer cells (19). Currently PF-03084014 is in phase I or phase II trials for the treatment of T-ALL, lymphoma, desmoid tumors, and fibromatosis (4,20,21).…”

Section: Introductionmentioning

confidence: 99%

Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1–Stat3

Zhang

et al. 2017

Molecular Cancer Therapeutics

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Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma, indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (g-secretase inhibitor) PF-03084014 in hepatocellular carcinoma. Hepatocellular carcinoma spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells. PF-03084014 reduced the hepatocellular carcinoma sphere-derived orthotopic tumor and blocked the hepatocellular carcinoma tumor liver to lung metastasis. We further tested the PF-03084014 in PDX models and confirmed the inhibition tumor growth effect. In addition, a low dose of PF-03084014 induced hepatocellular carcinoma sphere differentiation, resulting in chemosensitization. Antitumor activity was associated with PF-03084014-induced suppression of Notch1 activity, decreased Stat3 activation and phosphorylation of the Akt signaling pathway, and reduced epithelial-mesenchymal transition. These are the key contributors to the maintenance of cancer stemness and the promotion of cancer metastasis. Moreover, the Notch-Stat3 association was implicated in the clinical hepatocellular carcinoma prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of gamma-secretase inhibitors as a therapeutic option for the treatment of hepatocellular carcinoma.

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Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model

Cited by 37 publications

References 31 publications

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

EGFR Blockade Enriches for Lung Cancer Stem–like Cells through Notch3-Dependent Signaling

Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1–Stat3

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