RobinP
01-30-2006, 07:19 AM
INSULIN-LIKE GROWTH FACTOR-I-RECEPTOR-TARGETED THERAPY
The insulin-like growth factor (IGF) mitogenic signaling pathway is an attractive therapeutic target in breast cancer as its ligands and receptors are frequently overexpressed and implicated in cellular proliferation, transformation, and metastasis [115 (http://#R115)]. The IGF system is composed of ligands IGF-I and IGF-II, receptors IGF-IR and IGF-2R, and at least six IGF binding proteins (IGFBPs). High circulating levels of IGF-I are associated with a greater risk of breast cancer in premenopausal women, with an especially high risk among those younger than 50 years [116 (http://#R116)]. Elevated expression of IGF-II is linked to poor prognosis in breast cancer [117 (http://#R117)]. The IGF-IR is highly expressed and activated in breast tumors, and loss of heterozygosity is observed at IGF-2R (also called the mannose-6-phosphate receptor) [118 (http://#R118), 119 (http://#R119)]. Additionally, high levels of IGFs prevent apoptosis in response to chemotherapeutics and radiation, and overactive IGF-IR signaling is linked to resistance to trastuzumab in HER2-overexpressing breast cancer cells [120 (http://#R120), 121 (http://#R121)].
The importance of IGF signaling in breast cells is highlighted by evidence of crosstalk with ER signaling, such that transcription of IGF-I, IGF-II, IGF-IR, and IGFBPs is activated by the ER, which itself activates expression of IGF-I [120 (http://#R120)]. Treatment of breast cancer patients with the antiestrogens tamoxifen or raloxifene decreased the IGF-I/IGFBP-3 molar ratio such that lower amounts of circulating IGF-I were available for mitogenic signaling [122 (http://#R122), 123 (http://#R123)]. Somatostatin analogues also reduce IGF signaling by reducing IGF-I levels. RC-160 (vapreotide) significantly lowered IGF-I levels in heavily pretreated metastatic breast cancer patients but was unable to achieve objective tumor responses in phase II trials despite preclinical evidence of tumor inhibition [124 (http://#R124)]. Combination treatment with tamoxifen and the somatostatin analogue octreotide was also unable to achieve antitumor response [125 (http://#R125)]. However, a meta-analysis indicated that somatostatin analogues given as first-line therapy were associated with at least a partial tumor response with few side effects [126 (http://#R126)].
Several targeted therapies in preclinical development directly abrogate IGF signaling, including antisense strategies and antibody blockade. Antisense oligonucleotides against IGF-IR mRNA blocked proliferation of murine mammary carcinoma cells and demonstrated antitumor effects in vivo [127 (http://#R127)]. /math/alpha.gifIR3, a mouse anti-IGF-IR antibody, blocked IGF activity and tumor formation and growth in xenograft models of human breast cancer. However, /math/alpha.gifIR3 demonstrated some level of agonist activity as well as a cross-reaction with the insulin receptor. Furthermore, targeting IGF-IR alone may not be effective, since multiple receptors mediate IGF signaling [115 (http://#R115), 128 (http://#R128)-131 (http://#R131)]. Hence, targeting other components of the IGF pathway may be more beneficial.
IGFBPs bind and regulate circulating IGFs. Levels of IGFBP-1 and IGFBP-3 predicted recurrent disease at distant sites in breast cancer patients [132 (http://#R132)]. Subcutaneous delivery of a recombinant form of IGFBP-1 fused to polyethylene glycol (PEGBP-1) blocked IGF-I- and estrogen-mediated breast tumor growth in vivo [115 (http://#R115)]. Interestingly, IGFBP-3 restored sensitivity to trastuzumab in HER2+ breast cancer cells and, thus, may be a candidate for development to treat trastuzumab-resistant tumors [121 (http://#R121)].
see complete abstract at http://theoncologist.alphamedpress.org/cgi/content/full/8/1/5 (http://theoncologist.alphamedpress.org/cgi/content/full/8/1/5#R96)
#R96 (http://theoncologist.alphamedpress.org/cgi/content/full/8/1/5#R96)
And information for target therapies for IGF as well as therapies for p95 form of the her2 receptor:
José Baselga, MD images/spacer.gif images/spacer.gif
Chairman and Professor of Medicine
Medical Oncology Servoce
Vall d'Hebron University Hospital
Barcelona, Spain
2005-2006 BCRF Project:
Activation of a family of cell surface receptors, collectively known as tyrosine kinase receptors, plays a major role in cancer growth and progression. Upon activation, these receptors in turn activate a series of critical signaling pathways that ultimately are responsible for uncontrolled growth and survival. In recent years the signal transduction pathway downstream of tyrosine kinase receptors constituted by phosphatidylinositol 3-kinase (PI3-K), AKT and the mammalian target of rapamycin (mTOR) has been shown to be profoundly disrupted in breast cancer. Consequently, inhibiting this pathway has been proposed as a new therapeutic strategy against breast cancer. In particular, rapamycin and two rapamycin-like drugs (RAD001 and CCI-779) can inhibit mTOR downstream signaling. Emerging data from clinical trials have shown that advanced breast cancer patients whose tumors have progressed following standard therapies have experienced tumor regression with CCI-779 treatment. During the last year, Dr. Baselga and his colleagues have obtained evidence that the PI3-K/AKT/mTOR pathway is a promising target in patients with breast cancer. They have finalized the phase I pharmacodynamic and pharmacokinetic study with the mTOR-targeting agent RAD001, and have identified an optimal dose for further development. Their proposed combination trials with RAD001 and letrozole and with RAD001 and AEE788 are active and recruiting patients. Importantly, their studies have produced strong evidence that Insulin-like Growth Factor Receptor-1 (IGF-1R) pathway is an important survival regulator and that combined IGF-1R and mTOR blockage is a combination that deserves to be studied in the clinic. As a result, they will start soon a phase I study with an anti-IGF-1R monoclonal antibody in patients with breast cancer. Dr. Baselga’s group will undertake a new project in 2005-2006. They have identified a potential mechanism for the frequent lack of activity of the anti-HER2 monoclonal antibody trastuzumab in the treatment of patients with HER2 over-expressing breast cancer. They had previously reported that a significant proportion of breast cancers with HER2 amplification express an incomplete truncated form of the receptor, known as p95, that lacks the receptor?s extracellular portion. Their data suggests that these tumors are resistant to trastuzumab but may be sensitive instead to small molecule HER2 tyrosine kinase inhibitors (TKIs). They now aim to characterize the relationship between the expression of this abnormal form of the receptor and response to trastuzumab and HER2 TKIs. It is anticipated that their study will assist in choosing the right anti-HER2 therapy in patients expressing this truncated form of the receptor
The insulin-like growth factor (IGF) mitogenic signaling pathway is an attractive therapeutic target in breast cancer as its ligands and receptors are frequently overexpressed and implicated in cellular proliferation, transformation, and metastasis [115 (http://#R115)]. The IGF system is composed of ligands IGF-I and IGF-II, receptors IGF-IR and IGF-2R, and at least six IGF binding proteins (IGFBPs). High circulating levels of IGF-I are associated with a greater risk of breast cancer in premenopausal women, with an especially high risk among those younger than 50 years [116 (http://#R116)]. Elevated expression of IGF-II is linked to poor prognosis in breast cancer [117 (http://#R117)]. The IGF-IR is highly expressed and activated in breast tumors, and loss of heterozygosity is observed at IGF-2R (also called the mannose-6-phosphate receptor) [118 (http://#R118), 119 (http://#R119)]. Additionally, high levels of IGFs prevent apoptosis in response to chemotherapeutics and radiation, and overactive IGF-IR signaling is linked to resistance to trastuzumab in HER2-overexpressing breast cancer cells [120 (http://#R120), 121 (http://#R121)].
The importance of IGF signaling in breast cells is highlighted by evidence of crosstalk with ER signaling, such that transcription of IGF-I, IGF-II, IGF-IR, and IGFBPs is activated by the ER, which itself activates expression of IGF-I [120 (http://#R120)]. Treatment of breast cancer patients with the antiestrogens tamoxifen or raloxifene decreased the IGF-I/IGFBP-3 molar ratio such that lower amounts of circulating IGF-I were available for mitogenic signaling [122 (http://#R122), 123 (http://#R123)]. Somatostatin analogues also reduce IGF signaling by reducing IGF-I levels. RC-160 (vapreotide) significantly lowered IGF-I levels in heavily pretreated metastatic breast cancer patients but was unable to achieve objective tumor responses in phase II trials despite preclinical evidence of tumor inhibition [124 (http://#R124)]. Combination treatment with tamoxifen and the somatostatin analogue octreotide was also unable to achieve antitumor response [125 (http://#R125)]. However, a meta-analysis indicated that somatostatin analogues given as first-line therapy were associated with at least a partial tumor response with few side effects [126 (http://#R126)].
Several targeted therapies in preclinical development directly abrogate IGF signaling, including antisense strategies and antibody blockade. Antisense oligonucleotides against IGF-IR mRNA blocked proliferation of murine mammary carcinoma cells and demonstrated antitumor effects in vivo [127 (http://#R127)]. /math/alpha.gifIR3, a mouse anti-IGF-IR antibody, blocked IGF activity and tumor formation and growth in xenograft models of human breast cancer. However, /math/alpha.gifIR3 demonstrated some level of agonist activity as well as a cross-reaction with the insulin receptor. Furthermore, targeting IGF-IR alone may not be effective, since multiple receptors mediate IGF signaling [115 (http://#R115), 128 (http://#R128)-131 (http://#R131)]. Hence, targeting other components of the IGF pathway may be more beneficial.
IGFBPs bind and regulate circulating IGFs. Levels of IGFBP-1 and IGFBP-3 predicted recurrent disease at distant sites in breast cancer patients [132 (http://#R132)]. Subcutaneous delivery of a recombinant form of IGFBP-1 fused to polyethylene glycol (PEGBP-1) blocked IGF-I- and estrogen-mediated breast tumor growth in vivo [115 (http://#R115)]. Interestingly, IGFBP-3 restored sensitivity to trastuzumab in HER2+ breast cancer cells and, thus, may be a candidate for development to treat trastuzumab-resistant tumors [121 (http://#R121)].
see complete abstract at http://theoncologist.alphamedpress.org/cgi/content/full/8/1/5 (http://theoncologist.alphamedpress.org/cgi/content/full/8/1/5#R96)
#R96 (http://theoncologist.alphamedpress.org/cgi/content/full/8/1/5#R96)
And information for target therapies for IGF as well as therapies for p95 form of the her2 receptor:
José Baselga, MD images/spacer.gif images/spacer.gif
Chairman and Professor of Medicine
Medical Oncology Servoce
Vall d'Hebron University Hospital
Barcelona, Spain
2005-2006 BCRF Project:
Activation of a family of cell surface receptors, collectively known as tyrosine kinase receptors, plays a major role in cancer growth and progression. Upon activation, these receptors in turn activate a series of critical signaling pathways that ultimately are responsible for uncontrolled growth and survival. In recent years the signal transduction pathway downstream of tyrosine kinase receptors constituted by phosphatidylinositol 3-kinase (PI3-K), AKT and the mammalian target of rapamycin (mTOR) has been shown to be profoundly disrupted in breast cancer. Consequently, inhibiting this pathway has been proposed as a new therapeutic strategy against breast cancer. In particular, rapamycin and two rapamycin-like drugs (RAD001 and CCI-779) can inhibit mTOR downstream signaling. Emerging data from clinical trials have shown that advanced breast cancer patients whose tumors have progressed following standard therapies have experienced tumor regression with CCI-779 treatment. During the last year, Dr. Baselga and his colleagues have obtained evidence that the PI3-K/AKT/mTOR pathway is a promising target in patients with breast cancer. They have finalized the phase I pharmacodynamic and pharmacokinetic study with the mTOR-targeting agent RAD001, and have identified an optimal dose for further development. Their proposed combination trials with RAD001 and letrozole and with RAD001 and AEE788 are active and recruiting patients. Importantly, their studies have produced strong evidence that Insulin-like Growth Factor Receptor-1 (IGF-1R) pathway is an important survival regulator and that combined IGF-1R and mTOR blockage is a combination that deserves to be studied in the clinic. As a result, they will start soon a phase I study with an anti-IGF-1R monoclonal antibody in patients with breast cancer. Dr. Baselga’s group will undertake a new project in 2005-2006. They have identified a potential mechanism for the frequent lack of activity of the anti-HER2 monoclonal antibody trastuzumab in the treatment of patients with HER2 over-expressing breast cancer. They had previously reported that a significant proportion of breast cancers with HER2 amplification express an incomplete truncated form of the receptor, known as p95, that lacks the receptor?s extracellular portion. Their data suggests that these tumors are resistant to trastuzumab but may be sensitive instead to small molecule HER2 tyrosine kinase inhibitors (TKIs). They now aim to characterize the relationship between the expression of this abnormal form of the receptor and response to trastuzumab and HER2 TKIs. It is anticipated that their study will assist in choosing the right anti-HER2 therapy in patients expressing this truncated form of the receptor