Farnesyl transferase inhibitors--a novel therapy for breast cancer.

2001 ◽  
pp. 227-235 ◽  
Author(s):  
S R Johnston ◽  
L R Kelland
Keyword(s):  
Breast Cancer ◽  
Therapeutic Strategy ◽  
Biological Effects ◽  
Cell Signalling ◽  
Novel Therapy ◽  
Farnesyl Transferase ◽  
Ras Protein ◽  
Oncogenic Ras ◽  
Cancer Models ◽  
Farnesyl Transferase Inhibitors

Inhibitors of the enzyme farnesyl protein transferase prevent a key step in the post-translational processing of the Ras protein, and were developed initially as a therapeutic strategy to inhibit cell signalling in ras-transformed cells. As more has been learnt about the biological effects of farnesyl transferase inhibitors (FTIs) on cancer cells, it is clear that tumours without oncogenic ras mutations such as breast cancer may also be targets for FTI therapy. This article reviews the rationale for the development of FTIs, focussing on early preclinical data in breast cancer models together with preliminary results from the first phase II study of an FTI in advanced breast cancer.

Biological Effects and Mechanism of Action of Farnesyl Transferase Inhibitors

2000 ◽  
Vol 13 (10) ◽  
pp. 949-952 ◽  
Author(s):  
Hena R. Ashar ◽  
Lydia Armstrong ◽  
Linda J. James ◽  
Donna M. Carr ◽  
Kimberley Gray ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Biological Effects ◽  
Farnesyl Transferase ◽  
Farnesyl Transferase Inhibitors

scholarly journals Depletion of CD206+ Tumour Macrophages via a Peptide Targeted Star-Shaped Polyglutamate Inhibits Tumourigenesis and Metastatic Dissemination in Mouse Breast Cancer Models

2021 ◽  
Author(s):  
Anni Lepland ◽  
Alessio Malfanti ◽  
Uku Haljasorg ◽  
Eliana Asciutto ◽  
Monica Pickholz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapeutic Strategy ◽  
Primary Tumour ◽  
Foxp3 Expression ◽  
Expression Ratio ◽  
Cancer Models ◽  
Mouse Breast Cancer ◽  
Targeting Peptide ◽  
Poor Efficacy

Abstract Although many studies have explored the depletion of tumour-associated macrophages (TAMs) as a therapeutic strategy for solid tumours, currently available compounds suffer from poor efficacy and dose-limiting side effects. Here, we developed a novel TAM-depleting agent ("OximUNO") that specifically targets CD206+ TAMs and demonstrated efficacy in triple negative breast cancer (TNBC) mouse models. OximUNO comprises a star-shaped polyglutamate (St-PGA) decorated with the CD206-targeting peptide mUNO that carries the chemotherapeutic drug doxorubicin (DOX). In TNBC models, a fluorescently-labelled mUNO-decorated St-PGA homed to CD206+ TAMs within primary lesions and metastases. OximUNO exhibited no acute liver or kidney toxicity in vivo. Treatment with OximUNO reduced the progression of primary tumour lesions and pulmonary metastases, significantly diminished the number of CD206+ TAMs and increased the CD8/FOXP3 expression ratio (demonstrating immunostimulation). Our findings suggest the potential benefit of OximUNO as a TAM-depleting agent for TNBC treatment. Importantly, our studies also represent the first report of a peptide-targeted St-PGA as a targeted therapeutic nanoconjugate.

Farnesyl transferase inhibitors: the next targeted therapies for breast cancer?

2004 ◽  
Vol 11 (2) ◽  
pp. 191-205 ◽  
Author(s):  
R M O'Regan ◽  
F R Khuri
Keyword(s):  
Breast Cancer ◽  
Point Mutations ◽  
Receptor Activation ◽  
Ras Signaling ◽  
Farnesyl Transferase ◽  
Ras Mutations ◽  
Ras Activation ◽  
Farnesyl Transferase Inhibitors

The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways involved in cell proliferation and survival. Point mutations of ras oncogenes result in constitutively active Ras and have been shown to be oncogenic. However, ras activation can occur in the absence of ras mutations secondary to upstream receptor activation. The first important step in Ras activation is farnesylation by farnesyl transferase, and inhibitors of this enzyme have been demonstrated to inhibit Ras signaling, and have anti-tumor effects. However, it is now clear that farnesyl transferase inhibitors (FTIs) have activity independent of Ras, most likely due to effects on prenylated proteins downstream of Ras, which explains their activity in several malignancies, including breast cancer, where ras mutations are rare. Several FTIs are in clinical development for the treatment of solid tumors. Preclinical evidence suggests that FTIs can inhibit breast cancers in vitro and in vivo, and a phase II trial of the FTI, R115777, in patients with advanced breast cancer produced encouraging results. Based on prior successful outcomes with agents targeting the estrogen and epidermal growth factor receptor pathways in breast cancer, the FTIs, used alone or more likely with other agents, may be the next exciting targeted therapy in breast cancer.

scholarly journals Depletion of CD206+ Tumour Macrophages via a Peptide-Targeted Star-Shaped Polyglutamate Inhibits Tumourigenesis and Metastatic Dissemination in Mouse Breast Cancer Models

2021 ◽  
Author(s):  
Anni Lepland ◽  
Alessio Malfanti ◽  
Uku Haljasorg ◽  
Eliana Asciutto ◽  
Monica Pickholz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapeutic Strategy ◽  
Primary Tumour ◽  
Foxp3 Expression ◽  
Expression Ratio ◽  
Cancer Models ◽  
Mouse Breast Cancer ◽  
Targeting Peptide ◽  
Poor Efficacy

Although many studies have explored the depletion of tumour-associated macrophages (TAMs) as a therapeutic strategy for solid tumours, currently available compounds suffer from poor efficacy and dose-limiting side effects. Here, we developed a novel TAM-depleting agent ("OximUNO") that specifically targets CD206+ TAMs and demonstrated efficacy in triple negative breast cancer (TNBC) mouse models. OximUNO comprises a star-shaped polyglutamate (St-PGA) decorated with the CD206-targeting peptide mUNO that carries the chemotherapeutic drug doxorubicin (DOX). In TNBC models, a fluorescently-labelled mUNO-decorated St-PGA homed to CD206+ TAMs within primary lesions and metastases. OximUNO exhibited no acute liver or kidney toxicity in vivo. Treatment with OximUNO reduced the progression of primary tumour lesions and pulmonary metastases, significantly diminished the number of CD206+ TAMs and increased the CD8/FOXP3 expression ratio (demonstrating immunostimulation). Our findings suggest the potential benefit of OximUNO as a TAM-depleting agent for TNBC treatment. Importantly, our studies also represent the first report of a peptide-targeted St-PGA as a targeted therapeutic nanoconjugate.

Genomic analysis of C-type lectins

2002 ◽  
Vol 69 ◽  
pp. 59-72 ◽  
Author(s):  
Kurt Drickamer ◽  
Andrew J. Fadden
Keyword(s):  
Biological Effects ◽  
Cell Signalling ◽  
Genomic Analysis ◽  
Binding Activity ◽  
Immunoglobulin Superfamily ◽  
Carbohydrate Binding ◽  
Carbohydrate Recognition ◽  
Calcium Dependent ◽  
Binding Domains ◽  
Carbohydrate Recognition Domains

Many biological effects of complex carbohydrates are mediated by lectins that contain discrete carbohydrate-recognition domains. At least seven structurally distinct families of carbohydrate-recognition domains are found in lectins that are involved in intracellular trafficking, cell adhesion, cell–cell signalling, glycoprotein turnover and innate immunity. Genome-wide analysis of potential carbohydrate-binding domains is now possible. Two classes of intracellular lectins involved in glycoprotein trafficking are present in yeast, model invertebrates and vertebrates, and two other classes are present in vertebrates only. At the cell surface, calcium-dependent (C-type) lectins and galectins are found in model invertebrates and vertebrates, but not in yeast; immunoglobulin superfamily (I-type) lectins are only found in vertebrates. The evolutionary appearance of different classes of sugar-binding protein modules parallels a development towards more complex oligosaccharides that provide increased opportunities for specific recognition phenomena. An overall picture of the lectins present in humans can now be proposed. Based on our knowledge of the structures of several of the C-type carbohydrate-recognition domains, it is possible to suggest ligand-binding activity that may be associated with novel C-type lectin-like domains identified in a systematic screen of the human genome. Further analysis of the sequences of proteins containing these domains can be used as a basis for proposing potential biological functions.

The truncated somatostatin receptor sst5TMD4 stimulates the production of pro-angiogenic factors in in vitro and in vivo breast cancer models

2014 ◽  
Author(s):  
Raul M Luque ◽  
Mario Duran-Prado ◽  
David Rincon-Fernandez ◽  
Marta Hergueta-Redondo ◽  
Michael D Culler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Somatostatin Receptor ◽  
Angiogenic Factors ◽  
Cancer Models
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