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ABSTRACT: The central role played by the class I(A) phosphatidylinositol-3-kinase (PI3K) signaling node in human cancer is highlighted in the multiple mechanisms by which these signals become dysregulated. Many studies suggest that constitutive PI3K activation in human cancer contributes to drug resistance, including targeted agents and standard cytotoxic therapy. The combination of activation mechanisms and the multiple downstream cascades that emanate from the PI3K node contributes to the difficulty in measuring PI3K activation as a biomarker. Although many agents suppress the pathway in models, the challenge remains to translate this biology into a patient selection strategy (i.e., identify patients with "PI3K activated" tumors) and subsequently link this biomarker definition to drug responses in patients. The various genetic and epigenetic lesions resulting in pathway activation necessitate combined approaches using genetic, genomic, and protein biomarkers to accurately characterize "PI3K activated" tumors. Such a combined approach to pathway status can be assessed using a statistical stratification of patients in a randomized trial into "pathway on" and "pathway off" subsets to compare the treatment effect in each arm. Instead of considering individual biomarkers for their predictive ability, this strategy proposes the use of a collection of biomarkers to identify a specific "pathway on" patient population predicted to have clinical benefit from a pathway inhibitor. Here, we review the current understanding of the mechanisms of PI3K activation in breast cancer and discuss a pathway-based approach using PI3K as a predictive biomarker in clinical development, which is currently in use in a global phase 3 setting.
Breast Cancer Research and Treatment 11/2010; 124(1):1-11. · 4.43 Impact Factor
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Massimo Cristofanilli,
Vicente Valero,
Aroop Mangalik,
Melanie Royce,
Ian Rabinowitz,
Francis P Arena,
Joan F Kroener,
Elizabeth Curcio,
Claire Watkins, Sarah Bacus,
Elsa M Cora,
Elizabeth Anderson,
Patrick J Magill
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ABSTRACT: This phase II randomized trial evaluated the efficacy and tolerability of anastrozole combined with gefitinib or anastrozole with placebo in women with hormone receptor-positive metastatic breast cancer (MBC).
Postmenopausal women with hormone receptor-positive measurable or evaluable MBC who had not received prior endocrine therapy for this disease stage or who developed metastatic disease during/after adjuvant tamoxifen were eligible. The primary response variable was progression-free survival (PFS) and secondary response variables included clinical benefit rate, objective response rate, overall survival, safety and tolerability, and pharmacokinetics. Tumor biomarker evaluation was an exploratory objective.
Forty-three patients were randomized to anastrozole plus gefitinib and 50 patients were randomized to anastrozole plus placebo of a planned total of 174 patients (enrollment was prematurely discontinued due to slow recruitment). PFS for patients receiving the combination of anastrozole and gefitinib was longer than for patients receiving anastrozole plus placebo [hazard ratio (gefitinib/placebo), 0.55; 95% confidence interval, 0.32-0.94; median PFS, 14.7 versus 8.4 months]. The clinical benefit rate was 49% versus 34%, and the objective response rate was 2% versus 12% with anastrozole plus gefitinib and anastrozole plus placebo, respectively. No evidence of interaction between baseline biomarker levels and relative treatment effect was found. No unexpected adverse events were observed.
This small randomized study showed that anastrozole in combination with gefitinib is associated with a marked advantage in PFS compared with anastrozole plus placebo, and that the combination was tolerated in postmenopausal women with hormone receptor-positive MBC. Further investigation of epidermal growth factor receptor inhibition in combination with endocrine therapy may be warranted.
Clinical Cancer Research 03/2010; 16(6):1904-14. · 7.74 Impact Factor
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Wenle Xia, Sarah Bacus,
Intisar Husain,
Leihua Liu,
Sumin Zhao,
Zuguo Liu,
M Arthur Moseley,
J Will Thompson,
Franklin L Chen,
Kevin M Koch,
Neil L Spector
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ABSTRACT: The widespread clinical use of therapies targeting the ErbB2 receptor tyrosine kinase oncogene represents a significant advance in breast cancer treatment. However, the development of therapeutic resistance represents a dilemma limiting their clinical efficacy, particularly small-molecule tyrosine kinase inhibitors that block ErbB2 autophosphorylation and activation. Here, we show that lapatinib (GW572016), a highly selective, small-molecule inhibitor of the ErbB2 and epidermal growth factor receptor tyrosine kinases, which was recently approved for the treatment of advanced-stage ErbB2(+) breast cancer, unexpectedly triggered a cytoprotective stress response in ErbB2(+) breast cancer cell lines, which was mediated by the calcium-dependent activation of RelA, the prosurvival subunit of NF-kappaB. Abrogation of lapatinib-induced RelA activation using either small interfering RNA constructs or an intracellular calcium chelator enhanced the apoptotic effects of lapatinib in parental ErbB2(+) breast cancer cells and overcame therapeutic resistance to lapatinib in ErbB2(+) breast cancer lines that had been rendered resistant to lapatinib through chronic exposure to the drug, mimicking the clinical setting. In addition, analysis of changes in phospho-RelA expression in sequential clinical biopsies from ErbB2(+) breast cancers treated with lapatinib monotherapy revealed marginally statistically significant differences between responders and nonresponders, which was consistent with our preclinical findings. Elucidating the regulation of RelA by lapatinib in ErbB2(+) breast cancers, and showing its role in the development of therapeutic resistance to lapatinib, identifies another therapeutic target to overcome or prevent the onset of resistance to lapatinib in some women with ErbB2(+) breast cancers.
Molecular Cancer Therapeutics 02/2010; 9(2):292-9. · 5.23 Impact Factor
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ABSTRACT: ErbB2 targeted therapies represent an attractive strategy in breast cancer. Herceptin, an anti-ErbB2 monoclonal antibody, is an approved treatment for patients with ErbB2-overexpressing breast cancers. ErbB2 signaling can also be blocked using small molecule tyrosine kinase inhibitors, like Lapatinib, that compete with ATP for binding at the ErbB2 catalytic kinase domain. The principal adverse event attributable to Herceptin is cardiac toxicity. Data from clinical trials show that, unlike Herceptin, Lapatinib may have reduced cardiac toxicity. This study was conducted to elucidate pathways which may contribute to cardiac toxicity or survival using Lapatinib and Herceptin. Our results show that treatments directed to ErbB1/2 receptors using GW-2974 (a generic ErbB1/2 inhibitor) activated AMPK, a key regulator in mitochondrial energy production pathways in human cardiac cells and cancer cells. Although Herceptin downregulates tumor survival pathways, AMPK fails to be activated in tumor and cardiac cells. When treated in combination with TNFalpha, a known cytokine associated with cardiac toxicity, GW-2974 protected cardiac cells from cell death whereas Herceptin contributed to TNFalpha-induced cellular killing. Since activity of AMPK in cardiac cells is associated with stress induced survival in response to cytokines or energy depletion, cardiac toxicity by Herceptin may be a consequence of failure to induce stress-related survival mechanisms. Thus, the ability to activate AMPK after treatment with tyrosine kinase inhibitors may be a crucial factor for increased efficacy against the tumor and decreased risk of cardiomyopathy.
Cell cycle (Georgetown, Tex.) 04/2008; 7(12):1769-75. · 5.36 Impact Factor
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ABSTRACT: ABSTRACT: Overexpression of the human epidermal growth factor receptor (HER)-2 oncogenic receptor tyrosine kinase, which occurs in 25% of breast cancers, portends poor clinical outcome and consequently represents an attractive target for therapeutic intervention. Small molecule tyrosine kinase inhibitors that compete with ATP binding at the cytoplasmic catalytic kinase domain of HER-2 block autophosphorylation and activation of HER-2, resulting in inhibition of downstream proliferation and survival signals. These agents have exhibited clinical activity in patients with HER-2 overexpressing breast cancers. Here we review the development of HER-2 tyrosine kinase inhibitors, their mechanisms of action, their biological and clinical activities, their safety profile, and combination strategies including conventional cytotoxics and other targeted agents.
Breast cancer research: BCR 04/2007; 9(2):205. · 5.24 Impact Factor
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ABSTRACT: Trastuzumab antitumor activity in ErbB2-overexpressing breast cancers seems to be dependent upon the presence of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens phosphatidylinositol 3-kinase-Akt signaling. Consequently, PTEN deficiency, which occurs in 50% of breast cancers, predicts for resistance to trastuzumab monotherapy. Here, we show that lapatinib, a small-molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, exerts its antitumor activity in a PTEN-independent manner. Steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels were inhibited within 30 min following lapatinib but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of lapatinib). Whereas trastuzumab reportedly inhibits SRC phosphorylation (Y416), which in turn reduced SRC-ErbB2 protein interactions, lapatinib had no effect on either variable. To assess the potential functional role that PTEN might play in lapatinib antitumor activity, we selectively knocked down PTEN in BT474 and Au565 cells using small interfering RNA transfection. Loss of PTEN did not affect induction of tumor cell apoptosis by lapatinib in either cell line. In addition, lapatinib inhibited Akt phosphorylation in MDA-MB-468 cells, an ErbB1-expressing/ErbB2 non-overexpressing breast cancer line, despite their PTEN-null status. Moreover, patients with ErbB2-overexpressing inflammatory breast cancers responded to lapatinib monotherapy regardless of PTEN status. Thus, lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner. These data emphasize the importance of assessing PTEN status in tumors when selecting ErbB2-targeted therapies in patients with breast cancer.
Cancer Research 03/2007; 67(3):1170-5. · 7.86 Impact Factor
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Wenle Xia, Sarah Bacus,
Priti Hegde,
Intisar Husain,
Jay Strum,
Leihua Liu,
Georgina Paulazzo,
Ljuba Lyass,
Patricia Trusk,
Jason Hill,
Jennifer Harris,
Neil L Spector
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ABSTRACT: The development of acquired resistance to ErbB2 tyrosine kinase inhibitors limits the clinical efficacy of this class of cancer therapeutics. Little is known about the mechanism(s) of acquired resistance to these agents. Here we establish a model of acquired resistance to N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2 (methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (lapatinib), an inhibitor of ErbB2 and ErbB1 tyrosine kinases by chronically exposing lapatinib-sensitive ErbB2-overexpressing breast cancer cells to lapatinib, simulating the clinic where lapatinib is administered on a daily chronic basis. Analysis of baseline gene expression in acquired lapatinib-resistant and parental cells indicates estrogen receptor (ER) signaling involvement in the development of resistance. Using gene interference, we confirm that acquired resistance to lapatinib is mediated by a switch in cell survival dependence and regulation of a key antiapoptotic mediator from ErbB2 alone to codependence upon ER and ErbB2 rather than loss of ErbB2 expression or insensitivity of ErbB2 signaling to lapatinib. Increased ER signaling in response to lapatinib is enhanced by the activation of factors facilitating the transcriptional activity of ER, notably FOXO3a and caveolin-1. Importantly, we confirm that lapatinib induces ER signaling in tumor biopsies from patients with ErbB2-overexpressing breast cancers receiving lapatinib therapy. These findings provided the rationale for preventing the development of acquired resistance by simultaneously inhibiting both ER and ErbB2 signaling pathways. Establishing clinically relevant models of acquired resistance to ErbB2 kinase inhibitors will enhance therapeutic strategies to improve clinical outcomes for patients with ErbB2-overexpressing breast cancers.
Proceedings of the National Academy of Sciences 06/2006; 103(20):7795-800. · 9.68 Impact Factor
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Wenle Xia,
John Bisi,
Jay Strum,
Leihua Liu,
Kevin Carrick,
Katherine M Graham,
Amanda L Treece,
Mary Ann Hardwicke,
Michael Dush,
Qiaoyin Liao,
Ron E Westlund,
Sumin Zhao, Sarah Bacus,
Neil L Spector
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ABSTRACT: In breast cancer, overexpression of ErbB2 or aberrant regulation of survivin, a member of the inhibitor of apoptosis family, is associated with resistance to chemo/hormone therapy and predicts for a poor clinical outcome. A functional link between the two predictive factors has not been previously shown. Here, using genetic and pharmacologic approaches to block ErbB2 signaling, we show that ErbB2 regulates survivin protein expression in ErbB2-overexpressing breast cancer cells. Selective knockdown of ErbB2 using small interfering RNA markedly reduced survivin protein, resulting in apoptosis of ErbB2-overexpressing breast cancer cell lines such as BT474. Alternatively, inhibition of ErbB2 signaling using lapatinib (GW572016), a reversible small-molecule inhibitor of ErbB1/ErbB2 tyrosine kinases, at pharmacologically relevant concentrations, leads to marked inhibition of survivin protein with subsequent apoptosis. The effect of lapatinib on survivin seems to be predominantly posttranslational, mediated by ubiquitin-proteosome degradation as lactacystin, a proteosome inhibitor, reverses these effects. Furthermore, lapatinib down-regulated the expression of His-tagged survivin, which was under the transcriptional control of a heterologous promoter, providing additional evidence supporting a posttranslational mechanism of regulation. In contrast, trastuzumab and gefitinib failed to down-regulate survivin in ErbB2-overexpressing breast cancer cells. Importantly, the clinical relevance of these findings was illustrated in patients with ErbB2-overexpressing breast cancer whose clinical response to lapatinib was associated with marked inhibition of survivin in their tumors. These findings shed new light on the mechanism by which ErbB2 overexpression protects against apoptotic stimuli in breast cancer and identifies therapeutic interventions to improve clinical outcomes in these aggressive tumors.
Cancer Research 03/2006; 66(3):1640-7. · 7.86 Impact Factor
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Neil L Spector,
Wenle Xia,
Howard Burris,
Herbert Hurwitz,
E Claire Dees,
Afshin Dowlati,
Bert O'Neil,
Beth Overmoyer,
Paul K Marcom,
Kimberly L Blackwell,
Deborah A Smith,
Kevin M Koch,
Andrew Stead,
Steven Mangum,
Matthew J Ellis,
Leihua Liu,
Albert K Man,
Troy M Bremer,
Jennifer Harris, Sarah Bacus
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ABSTRACT: This was a pilot study to assess the biologic effects of lapatinib on various tumor growth/survival pathways in patients with advanced ErbB1 and/or ErbB2-overexpressing solid malignancies.
Heavily pretreated patients with metastatic cancers overexpressing ErbB2 and/or expressing ErbB1 were randomly assigned to one of five dose cohorts of lapatinib (GW572016) administered orally once daily continuously. The biologic effects of lapatinib on tumor growth and survival pathways were assessed in tumor biopsies obtained before and after 21 days of therapy. Clinical response was determined at 8 weeks.
Sequential tumor biopsies from 33 patients were examined. Partial responses occurred in four patients with breast cancer, and disease stabilization occurred in 11 others with various malignancies. Responders exhibited variable levels of inhibition of p-ErbB1, p-ErbB2, p-Erk1/2, p-Akt, cyclin D1, and transforming growth factor alpha. Even some nonresponders demonstrated varying degrees of biomarker inhibition. Increased tumor cell apoptosis (TUNEL) occurred in patients with evidence of tumor regression but not in nonresponders (progressive disease). Clinical response was associated with a pretreatment TUNEL score > 0 and increased pretreatment expression of ErbB2, p-ErbB2, Erk1/2, p-Erk1/2, insulin-like growth factor receptor-1, p70 S6 kinase, and transforming growth factor alpha compared with nonresponders.
Lapatinib exhibited preliminary evidence of biologic and clinical activity in ErbB1 and/or ErbB2-overexpressing tumors. However, the limited sample size of this study and the variability of the biologic endpoints suggest that further work is needed to prioritize biomarkers for disease-directed studies, and underscores the need for improved trial design strategies in early clinical studies of targeted agents.
Journal of Clinical Oncology 05/2005; 23(11):2502-12. · 18.37 Impact Factor
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ABSTRACT: OSI-774 is an inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR-TK) currently in clinical development. In preclinical models, the antitumor activity of OSI-774 was directly related to its ability to inhibit the EGFR-TK. On the basis of these data, we hypothesized that inhibition of the EGFR-TK will be required for this agent to be effective in the clinic. This study evaluated the pharmacodynamic effects of OSI-774 in normal skin tissues collected from patients treated with the agent in a Phase I study.
Patients with advanced cancer who were treated in a Phase I study of OSI-774 underwent a biopsy of normal skin epidermis at baseline and after the last dose of drug in the first course of treatment. The expression and activation of the EGFR, downstream signaling extracytoplasmatic-regulated kinase (Erk), and cell cycle regulator p27 were determined in paraffin-embedded skin tissues using an immunohistochemical method (IHC). The IHC data were analyzed using both a semiquantitative scoring system and an automatic absorbance quantitative IHC method. The number of cells with nuclear staining of p27 per 500 cells was determined. Plasma samples were collected to quantitate OSI-774 plasma concentrations.
A total of 56 skin specimens was collected from 28 patients treated with OSI-774 at doses ranging from 25 to 200 mg/day. There was a significant decrease in phospho-EGFR (Tyr 1173) expression as determined semiquantitatively with OSI-774 treatment [2.75 +/- 0.51 (mean +/- SD) pretreatment versus 2.36 +/- 0.76 after treatment, pair comparison P = 0.01]. The quantitative ratio [(phopho-EGFR/EGFR) x 100] of phospho-EGFR (Tyr1173) decreased from 64.16 +/- 36.58 pretreatment to 48.87 +/- 35.37 post-treatment (pair comparison, P = 0.02). No significant differences were observed in phospho-Erk (Thr202/Tyr204) expression. The mean number of cells with nuclear staining for p27 increased from 185 +/- 101 (mean +/- SD) pretreatment to 253 +/- 111 post-treatment (pair comparison P = 0.02). A total of 12 (42.8%), 7 (25%), and 14 (50%) patients had >25% variation in the ratio of phospho-EGFR (Tyr1173), phospho-Erk (Thr202/Tyr204), and p27 expression, respectively. Only changes in p27 expression were related to the administered dose of OSI-774.
OSI-774 exerted pharmacodynamic effects in skin tissues of 30-50% of patients treated with the agent. Up-regulation of p27, which is a downstream effect of EGFR inhibition, was dose related. Although there was a significant decrement in phospho-EGFR (Tyr1173), it was not related to the administered dose of OSI-774. On the basis of these findings and the relatively simple and reliable method to measure p27 expression, this biomarker appears to be the most promising and is being evaluated in Phase II studies as a predictor of clinical outcome.
Clinical Cancer Research 08/2003; 9(7):2478-86. · 7.74 Impact Factor
