Final results of a phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-line therapy after FOLFIRINOX or FOLFOX.

Ko, Andrew H.; Chiorean, E. Gabriela; Kwak, Eunice L.; Lenz, Heinz‐Josef; Nadler, Paul I.; Wood, Debra; Fujimori, M; Inada, Tetsuhi; Kouji, Hiroyuki; McWilliams, Robert R.

doi:10.1200/jco.2016.34.15_suppl.e15721

Cited by 59 publications

(44 citation statements)

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“…Cancer cells exhibit to mesenchymal characteristics before invasion. 33 Therefore, investigation of epithelial to mesenchymal transition-related genes is necessary to understand the effect of PD-0332991 on pancreatic cancer cells. 32 In our study, the Panc-1 and MiaPaCa-2 cells which have homozygote deletion in CDKN2A were used to understand the underline mechanism of the PD-0332991 on the regulation of cell proliferation and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Palbociclib, a selective CDK4/6 inhibitor, restricts cell survival and epithelial‐mesenchymal transition in Panc‐1 and MiaPaCa‐2 pancreatic cancer cells

Rencüzoğulları

Yerlikaya

Gürkan

et al. 2019

J of Cellular Biochemistry

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The mortality rate of pancreatic cancer has close parallels to its incidence rate because of limited therapeutics and lack of effective prognosis. Despite various novel chemotherapeutics combinations, the 5‐year survival rate is still under 5%. In the current study, we aimed to modulate the aberrantly activated PI3K/AKT pathway and epithelial‐mesenchymal transition (EMT) signaling with the treatment of CDK4/6 inhibitor PD‐0332991 (palbociclib) in Panc‐1 and MiaPaCa‐2 pancreatic cancer cells. It was found that PD‐0332991 effectively reduced cell viability and proliferation dose‐dependently within 24 hours. In addition, PD‐0332991 induced cell cycle arrest at the G1 phase by downregulation of aberrant expression of CDK4/6 through the dephosphorylation of Rb in each cell lines. Although PD‐0332991 treatment increased epithelial markers and decreased mesenchymal markers, the nuclear translocation of β‐catenin was not prevented by PD‐0332991 treatment, especially in MiaPaCa‐2 cells. Effects of PD‐0332991 on the regulation of PI3K/AKT signaling and its downstream targets such as GSK‐3 were cell type‐dependent. Although the activity of AKT was inhibited in both cell lines, the phosphorylation of GSK‐3β at Ser9 increased only in Panc‐1. In conclusion, PD‐0332991 induced cell cycle arrest and reduced the cell viability of Panc‐1 and MiaPaCa‐2 cells. However, PD‐0332991 differentially affects the regulation of the PI3K/AKT pathway and EMT process in cells due to its distinct influence on Rb and GSK‐3/β‐catenin signaling. Understanding the effect of PD‐0332991 on the aberrantly activated signaling axis may put forward a new therapeutic strategy to reduce the cell viability and metastatic process of pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Palbociclib, a selective CDK4/6 inhibitor, restricts cell survival and epithelial‐mesenchymal transition in Panc‐1 and MiaPaCa‐2 pancreatic cancer cells

Rencüzoğulları

Yerlikaya

Gürkan

et al. 2019

J of Cellular Biochemistry

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“…Upstream targeting of the Wnt pathway might not show efficacy in cancers with activating mutations of downstream components. PRI-724, an inhibitor of the interaction between b-catenin and its transcriptional coactivators, has been safely combined with gemcitabine in a phase 1b dose escalation study of 20 patients with R/R pancreatic cancer (Ko et al, 2016). The combination had modest clinical activity with disease stabilization in 8 (40%) patients.…”

Section: Inhibition Of Signaling Pathways Used By Cscsmentioning

confidence: 99%

Targeting Cancer Stemness in the Clinic: From Hype to Hope

et al. 2019

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Tumors are composed of non-homogeneous cell populations exhibiting varying degrees of genetic and functional heterogeneity. Cancer stem cells (CSCs) are capable of sustaining tumors by manipulating genetic and non-genetic factors to metastasize, resist treatment, and maintain the tumor microenvironment. Understanding the key traits and mechanisms of CSC survival provides opportunities to improve patient outcomes via improved prognostic models and therapeutics. Here, we review the clinical significance of CSCs and results of potential CSC-targeting therapies in various cancers. We discuss barriers to translating cues from pre-clinical models into clinical applications and propose new strategies for rational design of future anti-CSC trials.

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“…This molecule has shown promising results in the preclinical stage with pancreatic cancer cells. It has been proven to promote differentiation of CSCs, inhibition of stroma formation, and decrease the metastatic potential of cancer cells (111).…”

Section: Antagonists Of Wnt Co-activatormentioning

confidence: 99%

Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights

et al. 2019

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Wnt signaling is one of the central mechanisms regulating tissue morphogenesis during embryogenesis and repair. The pivot of this signaling cascade is the Wnt ligand, which binds to receptors belonging to the Frizzled family or the ROR1/ROR2 and RYK family. This interaction governs the downstream signaling cascade (canonical/non-canonical), ultimately extending its effect on the cellular cytoskeleton, transcriptional control of proliferation and differentiation, and organelle dynamics. Anomalous Wnt signaling has been associated with several cancers, the most prominent ones being colorectal, breast, lung, oral, cervical, and hematopoietic malignancies. It extends its effect on tumorigenesis by modulating the tumor microenvironment via fine crosstalk between transformed cells and infiltrating immune cells, such as leukocytes. This review is an attempt to highlight the latest developments in the understanding of Wnt signaling in the context of tumors and their microenvironment. A dynamic process known as immunoediting governs the fate of tumor progression based on the correlation of various signaling pathways in the tumor microenvironment and immune cells. Cancer cells also undergo a series of mutations in the tumor suppressor gene, which favors tumorigenesis. Wnt signaling, and its crosstalk with various immune cells, has both negative as well as positive effects on tumor progression. On one hand, it helps in the maintenance and renewal of the leucocytes. On the other hand, it promotes immune tolerance, limiting the antitumor response. Wnt signaling also plays a role in epithelial-mesenchymal transition (EMT), thereby promoting the maintenance of Cancer Stem Cells (CSCs). Furthermore, we have summarized the ongoing strategies used to target aberrant Wnt signaling as a novel therapeutic intervention to combat various cancers and their limitations.

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Final results of a phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-line therapy after FOLFIRINOX or FOLFOX.

Cited by 59 publications

References 0 publications

Palbociclib, a selective CDK4/6 inhibitor, restricts cell survival and epithelial‐mesenchymal transition in Panc‐1 and MiaPaCa‐2 pancreatic cancer cells

Palbociclib, a selective CDK4/6 inhibitor, restricts cell survival and epithelial‐mesenchymal transition in Panc‐1 and MiaPaCa‐2 pancreatic cancer cells

Targeting Cancer Stemness in the Clinic: From Hype to Hope

Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights

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