Abstract PO-042: FGFR1 expression correlates inversely with the in vitro and in vivo efficacy of FGFR inhibitors in pancreatic cancer

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

Download Full-text

The Revolutionary Roads to Study Cell–Cell Interactions in 3D In Vitro Pancreatic Cancer Models

Cancers ◽

10.3390/cancers13040930 ◽

2021 ◽

Vol 13 (4) ◽

pp. 930

Author(s):

Donatella Delle Cave ◽

Riccardo Rizzo ◽

Bruno Sainz ◽

Giuseppe Gigli ◽

Loretta L. del Mercato ◽

...

Keyword(s):

Pancreatic Cancer ◽

Therapeutic Response ◽

Three Dimensional ◽

Cellular Models ◽

Common Cancer ◽

Cancer Models ◽

Anti Cancer ◽

Tumor Environment

Pancreatic cancer, the fourth most common cancer worldwide, shows a highly unsuccessful therapeutic response. In the last 10 years, neither important advancements nor new therapeutic strategies have significantly impacted patient survival, highlighting the need to pursue new avenues for drug development discovery and design. Advanced cellular models, resembling as much as possible the original in vivo tumor environment, may be more successful in predicting the efficacy of future anti-cancer candidates in clinical trials. In this review, we discuss novel bioengineered platforms for anticancer drug discovery in pancreatic cancer, from traditional two-dimensional models to innovative three-dimensional ones.

Download Full-text

Intracellular localisation of Mycobacterium tuberculosis affects efficacy of the antibiotic pyrazinamide

Nature Communications ◽

10.1038/s41467-021-24127-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Pierre Santucci ◽

Daniel J. Greenwood ◽

Antony Fearns ◽

Kai Chen ◽

Haibo Jiang ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Host Cell ◽

Combination Chemotherapy ◽

In Vitro Activity ◽

In Vivo Efficacy ◽

Human Macrophages ◽

Ion Microscopy ◽

Intracellular Localisation

AbstractTo be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen, Mycobacterium tuberculosis. However, how host cell microenvironments affect antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among individual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy.

Download Full-text

Downregulation of GSTM2 enhances gemcitabine chemosensitivity of pancreatic cancer in vitro and in vivo

Pancreatology ◽

10.1016/j.pan.2020.12.008 ◽

2020 ◽

Author(s):

Lisi Peng ◽

Lu Zhuang ◽

Kun Lin ◽

Yao Yao ◽

Yang Zhang ◽

...

Keyword(s):

Pancreatic Cancer

Download Full-text

Oncogene APOL1 promotes proliferation and inhibits apoptosis via activating NOTCH1 signaling pathway in pancreatic cancer

Cell Death and Disease ◽

10.1038/s41419-021-03985-1 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Jiewei Lin ◽

Zhiwei Xu ◽

Junjie Xie ◽

Xiaxing Deng ◽

Lingxi Jiang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Signaling Pathway ◽

Density Lipoprotein ◽

Human Pancreatic Cancer ◽

Luciferase Reporter ◽

Notch1 Signaling ◽

In Vivo Experiments ◽

Notch1 Signaling Pathway

AbstractAPOL1 encodes a secreted high-density lipoprotein, which has been considered as an aberrantly expressed gene in multiple cancers. Nevertheless, the role of APOL1 in the regulatory mechanisms of pancreatic cancer remains unknown and should be explored. We identified APOL1 was abnormally elevated in human pancreatic cancer tissues compared with that in adjacent tissues and was associated with poor prognosis. The effects of APOL1 in PC cell proliferation, cell cycle, and apoptosis was verified via functional in vitro and in vivo experiments. The results showed that knockdown of APOL1 significantly inhibited the proliferation and promoted apoptosis of pancreatic cancer. In addition, we identified APOL1 could be a regulator of NOTCH1 signaling pathway using bioinformatics tools, qRT-PCR, dual-luciferase reporter assay, and western blotting. In summary, APOL1 could function as an oncogene to promote proliferation and inhibit apoptosis through activating NOTCH1 signaling pathway expression in pancreatic cancer; therefore, it may act as a novel therapeutic target for pancreatic cancer.

Download Full-text