Development of strategies for the use of anti-growth factor treatments

2005 ◽  
Vol 12 (Supplement_1) ◽  
pp. S173-S182 ◽  
Author(s):  
H E Jones ◽  
J M W Gee ◽  
K M Taylor ◽  
D Barrow ◽  
H D Williams ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
De Novo ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Cancer Cell Proliferation ◽  
Over Expression ◽  
Combination Strategies ◽  
Cancer Types ◽  
Epidermal Growth

Aberrant signalling through the epidermal growth factor receptor (EGFR) is associated with increased cancer cell proliferation, reduced apoptosis, invasion and angiogenesis. Over-expression of the EGFR is seen in a variety of tumours and is a rational target for antitumour strategies. Among the classes of agent targeting the EGFR are small-molecule inhibitors, which include gefitinib (IRESSA™), which acts by preventing EGFR phosphorylation and downstream signal transduction. De novo and acquired resistance, however, have been reported to gefitinib and here we describe evidence which indicates that the type II receptor tyrosine kinases (RTKs) insulin-like growth factor-I receptor (IGF-IR) and/or insulin receptor (InsR) play important roles in the mediation of responses to gefitinib in the de novo- and acquired-resistance phenotypes in several cancer types. Moreover, combination strategies that additionally target the IGF-IR/InsR can enhance the antitumour effects of gefitinib.

Growth factor receptor interplay and resistance in cancer

2006 ◽  
Vol 13 (Supplement_1) ◽  
pp. S45-S51 ◽  
Author(s):  
Helen E Jones ◽  
Julia M W Gee ◽  
Iain R Hutcheson ◽  
Janice M Knowlden ◽  
Denise Barrow ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
New Agents ◽  
Anti Cancer ◽  
Cancer Types ◽  
Epidermal Growth ◽  
High Level

Aberrant signalling through the epidermal growth factor receptor (EGFR) plays a major role in the progression and maintenance of the malignant phenotype and the receptor is therefore a rational anti-cancer target. A variety of approaches have been developed to specifically target the EGFR which include monoclonal antibodies and small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa). However, the recent clinical experience across a range of cancer types is revealing that despite the anti-EGFR agents demonstrating some anti-tumour activity, there is a high level of de novo and acquired resistance to such treatments and moreover, overexpression of the EGFR is clearly not the sole determinant of response to such therapies. Such adverse phenomena, which serve to limit the overall therapeutic impact of these new agents, implies the existence of a greater complexity involved in the regulation of EGFR signalling than was previously assumed. Indeed, evidence is accumulating which demonstrates that signalling interplay occurs between the EGFR, and the IGF-1 receptor (IGF-1R) and the review will focus on the emerging concept of growth factor pathway switching between these two receptors as a means of influencing the effectiveness of anti-EGFR agents such as gefitinib.

Growth factor pathway switching: implications for the use of gefitinib and trastuzumab

2006 ◽  
Vol 9 (7) ◽  
pp. 1-5 ◽  
Author(s):  
H. E. Jones ◽  
J. M. W. Gee ◽  
I. R. Hutcheson ◽  
R. I. Nicholson
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Clinical Problem ◽  
Over Expression ◽  
Signal Transduction Inhibitors ◽  
Epidermal Growth ◽  
Major Clinical Problem

Over-expression or aberrant signalling of the erbB family members epidermal growth factor receptor (EGFR) and HER2 (erbB2/neu) have been associated with the pathogenesis of the malignant phenotype. In addition, high levels of EGFR and HER2 expression have been shown to correlate with poor prognosis and also implicated in disease progression. Signal transduction inhibitors (STIs) have been developed with specifically target these receptors and include the small molecule tyrosine kinase inhibitor gefitinib (IressaTM) which targets the EGFR and the humanised monoclonal antibody trastuzumab (HerceptinTM), which has anti-tumour activity against HER2. Studies however, have indicated that de novo or acquired resistance to these agents is a major clinical problem. Cancer cells are highly adaptive and can readily switch from one receptor signalling pathway to another in order to maintain growth or cell survival, a process paradoxically, that in many instances is induced by the anti-tumour agents themselves, ultimately limiting their activity and promoting resistance. Evidence is accumulating which demonstrates that signalling interplay occurs between the EGFR/HER2 and the insulin-like growth factor -1 receptor (IGF-1R) and the article will focus on the growth factor pathway switching that occurs between these receptors which can influence the effectiveness gefitinib and trastuzumab.

Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy

2006 ◽  
Vol 13 (Supplement_1) ◽  
pp. S89-S97 ◽  
Author(s):  
Iain R Hutcheson ◽  
Janice M Knowlden ◽  
Helen E Jones ◽  
Rajpal S Burmi ◽  
Richard A McClelland ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Targeted Therapies ◽  
Cellular Response ◽  
De Novo ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Epidermal Growth

Aberrant epidermal growth factor receptor (EGFR) signalling, a key feature of a variety of human malignancies, can drive a range of mechanisms underlying tumour growth and progression, including increased cell proliferation, angiogenesis, metastasis and decreased apoptosis. Anti-EGFR therapies, as monotherapies and in combination with chemotherapy, have proved effective in inhibiting these processes both in the clinical and in the preclinical settings. However, only a small cohort of patients have derived significant benefit from this therapy, with both de novo and acquired resistance to these agents evident in a number of recent studies. If we are to improve the effectiveness of such targeted therapies, then there is an urgent need to understand the resistance mechanisms. Here, we describe both non-genomic and genomic mechanisms of resistance to the selective EGFR tyrosine kinase inhibitor gefitinib (IRESSA), which we have identified initially in an EGFR-positive tamoxifen-resistant MCF-7 breast cancer cell line, but more recently in other EGFR-positive cancer types. Importantly, we show that gefitinib, in common with anti-hormonal agents, is not a passive bystander in the cellular response to drug treatment, but plays an active role in promoting signalling pathways that serve to limit its anti-tumour activity and maintain the cellular cohort from which acquired resistance can ultimately evolve. These findings indicate that inductive signalling is an important determinant of response to EGFR-targeted therapies and deciphering such pathways may provide us with the opportunity to design more effective strategies to combat resistance mechanisms and improve response to initial therapy.

An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway

1994 ◽  
Vol 14 (1) ◽  
pp. 663-675
Author(s):  
M Santoro ◽  
W T Wong ◽  
P Aroca ◽  
E Santos ◽  
B Matoskova ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinases ◽  
Mammalian Cells ◽  
Egf Receptor ◽  
Biological Effects ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Dependent Signal ◽  
Epidermal Growth

A chimeric expression vector which encoded for a molecule encompassing the extracellular domain of the epidermal growth factor (EGF) receptor (EGFR) and the intracellular domain of the ret kinase (EGFR/ret chimera) was generated. Upon ectopic expression in mammalian cells, the EGFR/ret chimera was correctly synthesized and transported to the cell surface, where it was shown capable of binding EGF and transducing an EGF-dependent signal intracellularly. Thus, the EGFR/ret chimera allows us to study the biological effects and biochemical activities of the ret kinase under controlled conditions of activation. Comparative analysis of the growth-promoting activity of the EGFR/ret chimera expressed in fibroblastic or hematopoietic cells revealed a biological phenotype clearly distinguishable from that of the EGFR, indicating that the two kinases couple with mitogenic pathways which are different to some extent. Analysis of biochemical pathways implicated in the transduction of mitogenic signals also evidenced significant differences between the ret kinase and other receptor tyrosine kinases. Thus, the sum of our results indicates the existence of a ret-specific pathway of mitogenic signaling.

scholarly journals Long-term remission of a Her2/neu positive primary breast cancer under double monoclonal antibody therapy with trastuzumab and bevacizumab

2014 ◽  
Vol 48 (2) ◽  
pp. 184-188 ◽  
Author(s):  
Robert Königsberg ◽  
Julia Maierhofer ◽  
Tanja Steininger ◽  
Gabriele Kienzer ◽  
Christian Dittrich
Keyword(s):  
Breast Cancer ◽  
Case Report ◽  
Growth Factor ◽  
Antibody Therapy ◽  
Growth Factor Receptor ◽  
Over Expression ◽  
Single Target ◽  
Epidermal Growth ◽  
Endothelial Growth Factor

AbstractBackground. The attempt to act on several signalling pathways involved in tumour development simultaneously appears to be more attractive than attacking a single target structure alone. Vascular endothelial growth factor (VEGF) over-expression is frequently observed in human epidermal growth factor receptor 2 (Her2/neu) positive patients with breast cancer and over-expression of the proto-oncogene Her2/neu is associated with an up-regulation of VEGF.Case report. The case of a Her2/neu positive patient with breast cancer who refused cytotoxic chemotherapy with its potential side effects as well as mastectomy is presented. Our patient has been receiving the combined double administration of bevacizumab and trastuzumab for more than 4 years.Conclusions. This case report shows that (a) the combined double administration of bevacizumab and trastuzumab was be clinically effective. (b) The combination of bevacizumab and trastuzumab is safe and non-toxic. (c) Bevacizumab and trastuzumab can be used as a long-term application

Endocrine Resistance: What Do We Know?

2013 ◽  
pp. e37-e42 ◽  
Author(s):  
Todd W. Miller
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
De Novo ◽  
Early Stage ◽  
Effective Means ◽  
Endocrine Resistance ◽  
Large Body ◽  
Growth Factor Receptor ◽  
Oncogenic Signaling

Adjuvant therapy with antiestrogens targeting estrogen receptor α (ER) signaling prevents disease recurrence in many patients with early-stage ER+ breast cancer. However, a significant number of cases exhibit de novo or acquired endocrine resistance. While other clinical subtypes of breast cancer (HER2+, triple-negative) have disproportionately higher rates of mortality, ER+ breast cancer is responsible for at least as many deaths because it is the most common subtype. Therefore, identifying mechanisms that drive endocrine resistance is a high clinical priority. A large body of experimental evidence indicates that oncogenic signaling pathways underlie endocrine resistance, including growth factor receptor tyrosine kinases (HER2, epidermal growth factor receptor [EGFR], fibroblast growth factor receptor 1/2 [FGFR], insulin-like growth factor-1 receptor [IGF-1R]/ insulin receptor [InsR]), PI3K/AKT/ mTOR, MAPK/ERK, Src, CDK4/CDK6, and ER itself. Combined targeting of ER and such pathways may be the most effective means to combat antiestrogen resistance, and clinical trials testing such strategies show promising results. Herein, we discuss pathways associated with endocrine resistance, biomarkers that may be useful to predict response to targeted agents, and avenues for further exploration to identify strategies for the treatment of patients with endocrine-resistant disease.

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