Duke Comprehensive Cancer Center

Sun City Center, United States

Duke Comprehensive Cancer Center

Sun City Center, United States
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Araujo J.C.,University of Houston | Mathew P.,Tufts Medical Center | Armstrong A.J.,Duke Comprehensive Cancer Center | Braud E.L.,Springfield Clinic | And 7 more authors.
Cancer | Year: 2012

BACKGROUND: To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer (PC), the authors conducted a phase 1-2 trial combining docetaxel with dasatinib, an oral SRC inhibitor. METHODS: In phase 1, 16 men received dasatinib 50 to 120 mg once daily and docetaxel 60 to 75 mg/m 2 every 21 days. In phase 2, 30 additional men received dasatinib 100 mg once daily/docetaxel 75 mg/m 2 every 21 days. Efficacy endpoints included changes in prostate-specific antigen (PSA), measurable disease, bone scans, and markers of bone metabolism. Safety and pharmacokinetics were also studied. RESULTS: Combination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3-4 toxicity. Drug-drug interactions and a maximum tolerated dose were not identified. Durable 50% PSA declines occurred in 26 of 46 patients (57%). Of 30 patients with measurable disease, 18 (60%) had a partial response. Fourteen patients (30%) had disappearance of a lesion on bone scan. In bone marker assessments, 33 of 38 (87%) and 26 of 34 (76%) had decreases in urinary N-telopeptide or bone-specific alkaline phosphatase levels, respectively. Twenty-eight patients (61%) received single-agent dasatinib after docetaxel discontinuation and had stabilization of disease for an additional 1 to 12 months. CONCLUSIONS: The high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration-resistant PC. Parallel declines in levels of PSA and bone markers are consistent with cotargeting of epithelial and bone compartments of the cancer. Treatment with single-agent dasatinib following docetaxel cessation warrants further study. Copyright © 2011 American Cancer Society.

Pollak K.I.,Duke Comprehensive Cancer Center | Pollak K.I.,Duke University | Childers J.W.,University of Pittsburgh | Arnold R.M.,University of Pittsburgh
Journal of Palliative Medicine | Year: 2011

Palliative care relies heavily on communication. Although some guidelines do address difficult communication, less is known about how to handle conversations with patients who express ambivalence or resistance to such care. Clinicians also struggle with how to support patient autonomy when they disagree with patient choices. Motivational Interviewing (MI) techniques may help address these responses. Specifically, MI techniques such as reflective statements and summarizing can help reduce a patient's resistance, resolve patient ambivalence, and support patient autonomy. Not all the MI techniques are applicable, however, in part because palliative care clinicians do not guide patients to make particular choices but, instead, help patients make choices that are consistent with patient values. Some elements from MI can be used to improve the quality and efficacy of palliative care conversations. © Copyright 2011, Mary Ann Liebert, Inc. 2011.

Cao X.,Duke University | Zhu H.,Duke University | Zhu H.,University of North Carolina at Chapel Hill | Ali-Osman F.,Duke University | And 3 more authors.
Molecular Cancer | Year: 2011

Background: Epidermal growth factor receptor (EGFR) plays an essential role in normal development, tumorigenesis and malignant biology of human cancers, and is known to undergo intracellular trafficking to subcellular organelles. Although several studies have shown that EGFR translocates into the mitochondria in cancer cells, it remains unclear whether mitochondrially localized EGFR has an impact on the cells and whether EGFRvIII, a constitutively activated variant of EGFR, undergoes mitochondrial transport similar to EGFR.Results: We report that both receptors translocate into the mitochondria of human glioblastoma and breast cancer cells, following treatments with the apoptosis inducers, staurosporine and anisomycin, and with an EGFR kinase inhibitor. Using mutant EGFR/EGFRvIII receptors engineered to undergo enriched intracellular trafficking into the mitochondria, we showed that glioblastoma cells expressing the mitochondrially enriched EGFRvIII were more resistant to staurosporine- and anisomycin-induced growth suppression and apoptosis and were highly resistant to EGFR kinase inhibitor-mediated growth inhibition.Conclusions: These findings indicate that apoptosis inducers and EGFR-targeted inhibitors enhance mitochondrial translocalization of both EGFR and EGFRvIII and that mitochondrial accumulation of these receptors contributes to tumor drug resistance. The findings also provide evidence for a potential link between the mitochondrial EGFR pathway and apoptosis. © 2011 Cao et al; licensee BioMed Central Ltd.

Teoh D.G.K.,Duke Comprehensive Cancer Center | Secord A.A.,Duke Comprehensive Cancer Center | Secord A.A.,Duke University
Cancer Control | Year: 2011

Background: Angiogenesis is a critical component of tumor development and proliferation, and increased angiogenesis has been associated with a worse clinical outcome in a number of solid tumors, including ovarian cancer. Therefore, agents that target the angiogenic process are of considerable interest in the treatment of ovarian cancer. Methods: Studies evaluating the efficacy of antiangiogenic agents in ovarian cancer are reported. Antiangiogenic agents examined include vascular endothelial growth factor (VEGF) pathway inhibitors, including monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and a soluble receptor decoy, as well as inhibitors of other angiogenic factors and vascular disrupting agents. Results: The VEGF inhibitor bevacizumab has been shown to have efficacy in ovarian cancer in phase II trials and a progression-free survival advantage in one phase III trial. TKIs block the VEGF receptors and secondary angiogenic pathways and have shown activity in phase I and II trials. Alternative angiogenesis inhibitors include EphA2 inhibitors and a selective angiopoietin 1/2-neutralizing peptibody. Another strategy is to destroy the existing tumor vasculature, and a number of vascular disrupting agents are being studied in preclinical and phase I trials. Antiangiogenic agents have a unique side effect profile, likely due to inhibition of normal physiologic angiogenesis. Conclusions: Phase II and early phase III trials have demonstrated that antiangiogenic therapies have significant activity in ovarian cancer. The results of phase III trials in the front-line and recurrent settings will determine the extent of clinical benefit of antiangiogenic therapies in combination with chemotherapy. Antiangiogenic agents have a distinct side effect profile, and further studies are necessary to evaluate how to minimize the incidence of these events and to identify women most likely to benefit from these therapies.

Hartman Z.C.,Duke Comprehensive Cancer Center | Yang X.-Y.,Duke Comprehensive Cancer Center | Glass O.,Duke Comprehensive Cancer Center | Lei G.,Duke Comprehensive Cancer Center | And 6 more authors.
Cancer Research | Year: 2011

HER2 overexpression occurs in approximately 25% of breast cancers, where it correlates with poor prognosis. Likewise, systemic inflammation in breast cancer correlates with poor prognosis, although the process is not understood. In this study, we explored the relationship between HER2 and inflammation, comparing the effects of overexpressing wild-type or mutated inactive forms of HER2 in primary human breast cells. Wild-type HER2 elicited a profound transcriptional inflammatory profile, including marked elevation of interleukin-6 (IL-6) expression, which we established to be a critical determinant of HER2 oncogenesis. Mechanistic investigations revealed that IL-6 secretion induced by HER2 overexpression activated Stat3 and altered gene expression, enforcing an autocrine loop of IL-6/Stat3 expression. Both mouse and human in vivo models of HER2-amplified breast carcinoma relied critically on this HER2-IL-6-Stat3 signaling pathway. Our studies offer the first direct evidence linking HER2 to a systemic inflammatory mechanism that orchestrates HER2-mediated tumor growth. We suggest that the HER2-IL-6-STAT3 signaling axis we have defined in breast cancer could prompt new therapeutic or prevention strategies for treatment of HER2-amplified cancers. ©2011 AACR.

Zhu H.,Duke University | Cao X.,Duke University | Ali-Osman F.,Duke University | Ali-Osman F.,Duke Comprehensive Cancer Center | And 4 more authors.
Cancer Letters | Year: 2010

EGFR and its constitutively activated variant EGFRvIII are linked to glioblastoma resistance to therapy, the mechanisms underlying this association, however, are still unclear. We report that in glioblastoma, EGFR/EGFRvIII paradoxically co-expresses with p53-upregulated modulator of apoptosis (PUMA), a proapoptotic member of the Bcl-2 family of proteins primarily located on the mitochondria. EGFR/EGFRvIII binds to PUMA constitutively and under apoptotic stress, and subsequently sequesters PUMA in the cytoplasm. The EGFR-PUMA interaction is independent of EGFR activation and is sustained under EGFR inhibition. A Bcl-2/Bcl-xL inhibitor that mimics PUMA activity sensitizes EGFR/EGFRvIII-expressing glioblastoma cells to Iressa. Collectively, we uncovered a novel kinase-independent function of EGFR/EGFRvIII that leads to tumor drug resistance. © 2010 Elsevier Ireland Ltd.

Lo H.-W.,Duke University | Lo H.-W.,Duke Comprehensive Cancer Center | Cao X.,Duke University | Zhu H.,Duke University | And 3 more authors.
Molecular Cancer Research | Year: 2010

Emerging evidence indicates a novel mode of epidermal growth factor receptor (EGFR) signaling, notably, one involves EGFR nuclear translocalization and subsequent gene activation. To date, however, the significance of the nuclear EGFR pathway in glioblastoma (GBM) is unknown. Here, we report that EGFR and its constitutively activated variant EGFRvIII undergo nuclear translocalization in GBM cells, in which the former event requires EGF stimulation and the latter is constitutive. To gain insights into the effect of nuclear EGFR on gene expression in GBM, we created isogenic GBM cell lines, namely, U87MG-vector, U87MG-EGFR, and U87MG-EGFRdNLS that, respectively, express the control vector, EGFR, and nuclear entry-defective EGFR with a deletion of the nuclear localization signal (NLS). Microarray analysis shows that 19 genes, including cyclooxygenase-2 (COX-2), to be activated in U87MG-EGFR cells but not in U87MG-EGFRdNLS and U87MG-vector cells. Subsequent validation studies indicate that COX-2 gene is expressed at higher levels in cells with EGFR and EGFRvIII than those with EGFRdNLS and EGFRvIIIdNLS. Nuclear EGFR and its transcriptional cofactor signal transducer and activator of transcription 3 (STAT3) associate with the COX-2 promoter. Increased expression of EGFR/EGFRvIII and activated STAT3 leads to the synergistic activation of the COX-2 promoter. Promoter mutational analysis identified a proximal STAT3-binding site that is required for EGFR/EGFRvIII-STAT3-mediated COX-2 gene activation. In GBM tumors, an association exists between levels of COX-2, EGFR/EGFRvIII, and activated STAT3. Together, these findings indicate the existence of the nuclear EGFR/EGFRvIII signaling pathway in GBM and its functional interaction with STAT3 to activate COX-2 gene expression, thus linking EGFR-STAT3 and EGFRvIII-STAT3 signaling axes to proinflammatory COX-2 mediated pathway. ©2010 AACR.

Zhu H.,Duke University | Lo H.-W.,Duke University | Lo H.-W.,Duke Comprehensive Cancer Center
Current Genomics | Year: 2010

Sonic hedgehog (Shh) signaling is critically important for embryogenesis and other cellular processes in which GLI transcription factors mediate the terminal effects of the pathway. GLI1, in particular, plays a significant role in human cancers. Consequently, GLI1 and its upstream positive regulator Smoothened (SMO) are important targets of anti-cancer therapy and several SMO-targeted small molecule inhibitors are being evaluated clinically. Emerging exciting evidence reveals a high level of complexity that lies within the GLI1-mediated pathway. For example, a recent study provided evidence linking the polymorphic GLI1 variants Q1100/E1100 to chronic inflammatory bowel diseases. Two recent reports uncovered the existence of two novel human GLI1 isoforms that differ structurally and functionally from the wild-type GLI1 identified over two decades ago. Interestingly, although both are products of alternative splicing, GLI1ΔN and tGLI1 (truncated GLI1) isoforms are predominantly expressed in normal and malignant tissues, respectively. In addition to these important discoveries, gene expression profiling studies have identified a number of novel wild-type GLI1 and tGLI1 target genes, linking wild-type GLI1 to tumor progression and therapeutic resistance, and tGLI1 to tumor invasion and migration. In light of these new insights, this review will provide a comprehensive overview on GLI1 polymorphisms and the three members of the GLI1 family of proteins, and their impacts on human diseases, including, cancers. © 2010 Bentham Science Publishers Ltd.

Shelby R.A.,Duke University | Abernethy A.P.,Duke University | Abernethy A.P.,Duke Comprehensive Cancer Center
Supportive Care in Cancer | Year: 2011

Purpose: Sexual concerns are understudied and undertreated for patients with lung cancer. Objectives were to: (1) assess sexual concerns in lung cancer patients and examine differences by age and gender; (2) examine stability of sexual concerns over time; and (3) evaluate whether sexual concerns in lung cancer patients are significantly related to physical and emotional symptoms. Materials and methods: Data were collected from lung cancer patients during four outpatient clinic visits over 6 months. Measures included sexual concerns (reduced sexual enjoyment, interest, or performance), fatigue (FACIT Fatigue Scale), shortness of breath, and emotional distress (acute distress, despair; Patient Care Monitor). Linear mixed model analyses were conducted. Results: Sexual concerns were common, with 52% of patients reporting at least mild sexual concerns and were stable. Sexual concerns were significantly associated with physical and emotional symptoms; particularly strong relationships were found between sexual concerns and shortness of breath and emotional distress. Age moderated the relationship between both fatigue and shortness of breath and sexual concerns; gender moderated the relationship between emotional distress and sexual concerns. Conclusions: Self-reported sexual concerns are common in people with lung cancer, are stable, and are related significantly to physical and emotional symptoms; age and gender influence the distress associated with sexual symptoms in this population. Better attention to patient concerns, treatment, and more research are clearly needed. © 2010 Springer-Verlag.

Armstrong A.J.,Duke Comprehensive Cancer Center | Tannock I.F.,University of Toronto | Wit R.d.,Erasmus Medical Center | George D.J.,Duke Comprehensive Cancer Center | And 2 more authors.
European Journal of Cancer | Year: 2010

Aims of the study: There are no known predictive factors of response in men receiving chemotherapy for metastatic castration-resistant prostate cancer (mCRPC). We investigated pre-treatment factors that predicted a ≥30% PSA decline (30% PSAD) within 3 months of starting chemotherapy, and assessed performance of a risk group classification in predicting PSA declines and overall survival (OS) in men with mCRPC. Methods: In TAX327, 1006 men with mCRPC were randomized to receive docetaxel (D) in two schedules, or mitoxantrone (M), each with prednisone: 989 provided data on PSA decline within 3 months. Predictive factors for a 30% PSAD were identified using multivariable regression in D-treated men (n = 656) and validated in M-treated men (n = 333). Results: Four independent risk factors predicted 30% PSAD: pain, visceral metastases, anaemia and bone scan progression. Risk groups (good: 0-1 factors, intermediate: 2 factors and poor: 3-4 factors) were developed with median OS of 25.7, 18.7 and 12.8 months (p < 0.0001); 30% PSAD in 78%, 66% and 58% of men (p < 0.001); and measurable disease response in 19%, 9% and 5% of men (p = 0.018), respectively. In the validation cohort, similar predictive ability was noted for 30% PSAD, tumour response and OS. PCWG2 subtypes were also predictive but resulted in unequal grouping. C-indices were 0.59 and 0.62 for 30% PSAD and OS in the validation dataset, respectively. Conclusions: Risk groups have been identified and validated that predict PSAD and OS in men with mCRPC and may facilitate evaluation of new systemic regimens warranting definitive testing in comparison with docetaxel and prednisone. Prospective validation of this classification system is needed. © 2009 Elsevier Ltd. All rights reserved.

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