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  • American Association for Cancer Research (AACR)  (7)
  • 2005-2009  (7)
  • 2009  (7)
  • 1
    Online Resource
    Online Resource
    Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 8 ( 2009-04-15), p. 2942-2948
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 8 ( 2009-04-15), p. 2942-2948
    Abstract: Purpose: Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether adding tipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified. Experimental Design: Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p)-signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib during the first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (α = 0.05, β = 0.10). Results: Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01). Conclusion: Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-2658
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
    Online Resource
    Online Resource
    Phase I Biodistribution and Pharmacokinetic Study of Lewis Y–Targeting Immunoconjugate CMD-193 in Patients with Advanced Epithelial Cancers
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 21 ( 2009-11-01), p. 6709-6715
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 21 ( 2009-11-01), p. 6709-6715
    Abstract: Purpose: This phase I study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 [a humanized anti–Lewis Y (Ley) antibody conjugated with calicheamicin in patients with advanced cancers expressing the Ley antigen. Experimental Design: The primary objectives were to determine biodistribution and pharmacokinetics of CMD-193. Secondary objectives included response rates and change in tumor metabolism. Patients with progressive, measurable, and Ley positive malignancies were eligible for enrollment in one of two dose cohorts, 1.0 and 2.6 mg/m2. The first cycle was trace labeled with 111In for biodistribution assessment using γ camera imaging. Subsequent cycles were administered every 3 weeks up to a maximum of six cycles, depending on toxicity and response. Pharmacokinetic analysis was based on radioassay and ELISA. Results: Nine patients were enrolled in the study. Biodistribution images showed initial blood pool activity, followed by markedly increased hepatic uptake by day 2, and fast blood clearance in all patients. There was low uptake in tumor in all patients. The overall T½β of 111In-CMD-193 was 102.88 ± 35.67 hours, with no statistically significant difference between the two dose levels. One patient had a partial metabolic response on 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET) after four cycles, but no radiological responses were observed. Myelosuppression and effects on liver function were the most significant adverse effects. Conclusions: CMD-193 shows rapid blood clearance and increased hepatic uptake compared with prior studies of the parental antibody hu3S193. These results highlight the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics to assist in clinical development. (Clin Cancer Res 2009;15(21):6709–15)
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-09-0536
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
    Online Resource
    Online Resource
    Immunogenicity and Antitumor Effects of Vaccination with Peptide Vaccine +/− Granulocyte-Monocyte Colony-Stimulating Factor and/or IFN-α2b in Advanced Metastatic Melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 4 ( 2009-02-15), p. 1443-1451
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 4 ( 2009-02-15), p. 1443-1451
    Abstract: Purpose: No therapy has ever shown prolongation of survival in stage IV metastatic melanoma. The association of cytokine-induced autoimmunity with improved prognosis led us to investigate the effect of multi-epitope melanoma vaccines alone and in combination with cytokines in this Eastern Cooperative Oncology Group multicenter phase II trial. Experimental Design: Eligible patients were required to have failed prior therapies and to be HLA-A2 positive. Three HLA class I-restricted lineage antigen epitopes were administered in a factorial 2 × 2 design. Peptide vaccine alone (arm A), or combined with granulocyte-monocyte colony-stimulating factor (GM-CSF; Immunex) 250 μg/d subcutaneously for 14 of 28 days each month (arm B), or combined with IFN-α2b (Intron A; Schering-Plough) 10 million units/m2 three times a week (arm C), or combined with both IFN-α2b and GM-CSF (arm D). The primary endpoint was immune response measured by enzyme-linked immunospot assay; secondary endpoints were clinical antitumor response, disease-free survival, and overall survival. Results: One hundred twenty patients enrolled and 115 patients were analyzed. Immune responses to at least one melanoma antigen were observed in 26 of 75 (35%) patients with serial samples. Neither IFN-α2b nor GM-CSF significantly improved immune responses. Six objective clinical responses were documented. At a median follow-up of 25.4 months, the median overall survival of patients with vaccine immune response was significantly longer than that of patients with no immune response (21.3 versus 13.4 months; P = 0.046). Conclusion: Immune response to vaccination correlates with prolonged survival in patients with metastatic melanoma and is not enhanced by immunomodulatory cytokines as tested in this trial.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-1231
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 4
    Online Resource
    Online Resource
    Active Notch1 Confers a Transformed Phenotype to Primary Human Melanocytes
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 13 ( 2009-07-01), p. 5312-5320
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 13 ( 2009-07-01), p. 5312-5320
    Abstract: The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf, yet clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions showed that Notch activity is significantly higher in melanomas than their nontransformed counterparts. The use of a constitutively active, truncated Notch transgene construct (NIC) was exploited to determine if Notch activation is a “driving” event in melanocytic transformation or instead a “passenger” event associated with melanoma progression. NIC-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma, such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. NIC-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth, suggesting that Notch alone is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene. This new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease. [Cancer Res 2009;69(13):5312–20]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-3767
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    Adjuvant Trastuzumab Induces Ventricular Remodeling Despite Aerobic Exercise Training
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 15 ( 2009-08-01), p. 4963-4967
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 15 ( 2009-08-01), p. 4963-4967
    Abstract: Purpose: To examine the effect of aerobic training in mitigating trastuzumab-mediated left ventricular (LV) remodeling in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Experimental Design: Seventeen women (53 ± 7 years) with HER2-positive breast cancer did aerobic training during the first 4 months of adjuvant trastuzumab. Peak oxygen consumption and magnetic resonance imaging assessment of LV volumes, mass, and rest and peak (dobutamine stress) ejection fraction were assessed before and after 4 months of trastuzumab. Results: Participants attended 59% ± 32% of prescribed exercise sessions at 78% ± 6% of peak heart rate. Peak exercise heart rate, systolic and diastolic blood pressure, power output, and oxygen consumption were not different after training (all P-values & gt; 0.05). Exercise adherence predicted change in peak oxygen consumption (r = 0.77; P = 0.000). Resting end-diastolic (pre: 120 ± 23 mL versus post: 133 ± 16 mL) and end-systolic volumes (pre: 44 ± 12 mL versus post: 55 ± 11 mL) and mass (pre: 108 ± 21 g versus post: 114 ± 18 g) increased, whereas ejection fraction (pre: 64% ± 4% versus post: 59% ± 4%) decreased from baseline to post-intervention (all P-values & lt; 0.05). Peak ejection fraction was lower after 4 months (pre: 79 ± 4 versus post: 76 ± 6%; P = 0.087). Conclusion: Initiation of adjuvant trastuzumab therapy is associated with LV cavity dilation and reduced ejection fraction despite aerobic exercise training. The long-term consequences of trastuzumab-induced LV remodeling and the means to prevent LV dysfunction require further study.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-09-0628
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 6
    Online Resource
    Online Resource
    Decision Making about Cancer Screening: An Assessment of the State of the Science and a Suggested Research Agenda from the ASPO Behavioral Oncology and Cancer Communication Special Interest Group
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 18, No. 11 ( 2009-11-01), p. 3133-3137
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 18, No. 11 ( 2009-11-01), p. 3133-3137
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-18-11-ASPO
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 7
    Online Resource
    Online Resource
    Dose-Dependent Increases in Circulating TGF-α and Other EGFR Ligands Act As Pharmacodynamic Markers for Optimal Biological Dosing of Cetuximab and Are Tumor Independent
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 7 ( 2009-04-01), p. 2397-2405
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 7 ( 2009-04-01), p. 2397-2405
    Abstract: Purpose: The objective of this study was to characterize treatment-induced circulating ligand changes during therapy with epidermal growth factor receptor (EGFR) inhibitors and evaluate their potential as surrogate indicators of the optimal biological dose. Experimental Design: Conditioned medium from human tumor cell lines, ascites fluid from tumor xenografts, and plasma samples from normal mice, as well as colorectal cancer patients, were assessed for ligand elevations using ELISA, following treatment with cetuximab (Erbitux), an anti–mouse EGFR neutralizing antibody, or a small-molecule EGFR tyrosine kinase inhibitor. Results: A rapid elevation in human transforming growth factor α (TGF-α) was observed in all cell lines after treatment with cetuximab, but not with small-molecule inhibitors. The elevation showed a dose-response effect and plateau that corresponded to the maximal decrease in A431 proliferation in vitro and HT29 tumor growth in vivo. The TGF-α increase was exacerbated by ongoing ligand production and cleavage from the plasma membrane but did not involve transcriptional up-regulation of TGF-α or the matrix metalloproteinase tumor necrosis factor-α–converting enzyme/ADAM17. Elevations in plasma TGF-α, amphiregulin, and epiregulin were also detected in normal mice treated with an anti–mouse EGFR monoclonal antibody, illustrating a host tissue–dependent component of this effect in vivo. Finally, circulating TGF-α increased in the plasma of six patients with EGFR-negative colorectal tumors during cetuximab treatment. Conclusions: Treatment-induced increases in circulating ligands, particularly TGF-α, should be serially assessed in clinical trials of anti-EGFR therapeutic antibodies as potential biomarkers to aid in determination of the optimal biological dose.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-1627
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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