Hillman Cancer Center Research Pavilion

Pittsburgh, PA, United States

Hillman Cancer Center Research Pavilion

Pittsburgh, PA, United States
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Jie H.-B.,University of Pittsburgh | Schuler P.J.,University of Pittsburgh | Schuler P.J.,University of Duisburg - Essen | Lee S.C.,University of Pittsburgh | And 7 more authors.
Cancer Research | Year: 2015

The EGFR-targeted antibody cetuximab is effective against head and neck cancer (HNSCC), but in only 15% to 20% of patients, and the variability and extent of cetuximab-mediated cellular immunity is not fully understood. We hypothesized that regulatory T cells (Treg) may exert a functional and clinical impact on antitumor immunity in cetuximab-treated individuals. The frequency, immunosuppressive phenotype, and activation status of Treg and natural killer (NK) cells were analyzed in the circulation and tumor microenvironment of cetuximab-treated patients with HNSCC enrolled in a novel neoadjuvant, single-agent cetuximab clinical trial. Notably, cetuximab treatment increased the frequency of CD4+FOXP3+ intratumoral Treg expressing CTLA-4, CD39, and TGFb. These Treg suppressed cetuximab-mediated antibodydependent cellular cytotoxicity (ADCC) and their presence correlated with poor clinical outcome in two prospective clinical trial cohorts. Cetuximab expanded CTLA-4+FOXP3+ Treg in vitro, in part, by inducing dendritic cell maturation, in combination with TGFb and T-cell receptor triggering. Importantly, cetuximab-activated NK cells selectively eliminated intratumoral Treg but preserved effector T cells. In ex vivo assays, ipilimumab targeted CTLA- 4+ Treg and restored cytolytic functions of NK cells mediating ADCC. Taken together, our results argue that differences in Tregmediated suppression contribute to the clinical response to cetuximab treatment, suggesting its improvement by adding ipilimumab or other strategies of Treg ablation to promote antitumor immunity. © 2015 American Association for Cancer Research.

Ferris R.L.,Hillman Cancer Center Research Pavilion | Kraus D.H.,New Hill
Clinical and Experimental Metastasis | Year: 2012

Metastasis to the regional lymph node is the most important prognostic indicator for the outcomes of patients with sold cancer. In general, it is well recognized that cancer development is genetically determined with progression from the microenvironment of the primary tumor site, oftentimes via the SLN gateway, to the distant sites. In about 20 % of the time, the cancer cells may spread directly through the blood vascular system to the distant sites. Thus, in general, cancer progression is consistent with Hellman's spectrum theory in that development of nodal and systemic metastasis from a localized cancer growth is a progressive process. Cancer proliferation within the tumor microenvironment may give rise to increased tumor heterogeneity, which is further complicated by its continuous change through its evolution within the host in a Darwinian sense. It is crucial to understand the molecular process of lymphangiogenesis and hemangiogenesis in the tumor microenvironment with respect to the initial steps of cancer cells entering into the lymphatic and vascular systems so that rational therapy can be developed to curb the process of specific routes of metastasis. This chapter elucidates the role of lymphatics, nodal metastasis and antitumor immunity. We present novel immune targets in nodal metastases, the importance of the lymph node as a pre-metastatic niche, and immune-related proteins as biomarkers of metastasis. © Springer Science+Business Media B.V. 2012.

Yu J.,University of Pittsburgh | Yu J.,Hillman Cancer Center Research Pavilion
Translational Cancer Research | Year: 2013

Radiation and chemotherapy remain the most effective and widely used cancer treatments. These treatments cause DNA damage and selectively target rapidly proliferating cells such as cancer cells, as well as inevitably cause damage to normal tissues, particularly those undergoing rapid self renewal. The side effects associated with radiation and chemotherapy are most pronounced in the hematopoietic (HP) system and gastrointestinal (GI) tract. These tissues are fast renewing and have a well-defined stem cell compartment that plays an essential role in homeostasis, and in treatment-induced acute injury that is dose limiting. Using recently defined intestinal stem cell markers and mouse models, a great deal of insight has been gained in the biology of intestinal stem cells (ISCs), which will undoubtedly help further mechanistic understanding of their injury. This review will cover historic discoveries and recent advances in the identification and characterization of intestinal stem cells, their responses to genotoxic stress, and a new crypt and intestinal stem cell culture system. The discussion will include key pathways regulating intestinal crypt and stem cell injury and regeneration caused by cancer treatments, and strategies for their protection. The focus will be on the acute phase of cell killing in mouse radiation models, where our understanding of the mechanisms in relation to intestinal stem cells is most advanced and interventions appear most effective. © 2011-2016 Translational Cancer Research.

Donnenberg V.S.,University of Pittsburgh | Donnenberg A.D.,University of Pittsburgh | Donnenberg A.D.,Hillman Cancer Center Research Pavilion
Journal of Clinical Pharmacology | Year: 2015

The cancer stem cell paradigm, the epithelial-to-mesenchymal transition and its converse, the mesenchymal-to-epithelial transition, have reached convergence. Implicit in this understanding is the notion that cancer cells can change state, and with such change come bidirectional alterations in motility, proliferative activity, and drug resistance. As such, tumors present a moving target for antineoplastic therapy. This article will review the evolving adult stem cell paradigm and how changes in our understanding of the bidirectional nature of cancer cell differentiation may affect the selection and timing of antineoplastic therapy. The goal is to determine how to best administer therapies potentially targeted against the cancer stem cell state in the context of established treatment regimens, and to evaluate long-term effects beyond tumor regression. © 2015, The American College of Clinical Pharmacology.

Xiao D.,University of Pittsburgh | Singh S.V.,University of Pittsburgh | Singh S.V.,Hillman Cancer Center Research Pavilion
Pharmaceutical Research | Year: 2010

Purpose. The present study was undertaken to determine efficacy of phenethyl isothiocyanate (PEITC) for sensitization of androgen-independent human prostate cancer cells (AIPC) to Docetaxel-induced apoptosis using cellular and xenograft models. Methods. Cell viability was determined by trypan blue dye exclusion, assay. Microscopy and DNA fragmentation assay were performed, to quantify apoptotic cell death in cultured cells. Protein levels were determined by immunoblotting. PC-3 prostate cancer xenograft model was utilized to determine in vivo efficacy of the PEITC and/or Docetaxel treatments. Results. Pharmacologic concentrations of PEITC augmented Docetaxel-induced apoptosis in PC-3 and DU145 cells in association with suppression of Bcl-2 and XIAP protein levels and induction of Bax and Bak. The PEITC-Docetaxel combination was markedly more efficacious against PC-3 xenograft in vivo compared with PEITC or Docetaxel alone. Significantly higher counts of apoptotic bodies were also observed in tumor sections from mice treated with the PEITC-Docetaxel combination compared with PEITC or Docetaxel alone. The PEITC and/or Docetaxel-mediated changes in the levels of apoptosis regulating proteins in the tumor were generally consistent with the molecular alterations observed in cultured cells. Conclusion. These results offer obligatory impetus to test PEITC-Docetaxel combination for the treatment of AIPC in a clinical setting. © 2010 Springer Science+Husiness Media, LLC.

Stephenson R.M.,University of Pittsburgh | Lim C.M.,University of Pittsburgh | Matthews M.,VentiRx | Dietsch G.,VentiRx | And 3 more authors.
Cancer Immunology, Immunotherapy | Year: 2013

Background: Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that prolongs survival in the treatment for head and neck cancer (HNC), but only in 10-20 % of patients. An immunological mechanism of action such as natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been suggested. We investigated the effects of activating toll-like receptor (TLR)-8 to enhance activity of cetuximab-stimulated, FcγR-bearing cells. Objective: To determine the capability of TLR8-stimulation to enhance the activation and function of NK cells and dendritic cells (DC) in the presence of cetuximab-coated HNC cells. Methods: Peripheral blood mononuclear cells (PBMC), NK, DC, and CD8+ T cells were isolated and analyzed using 51Cr release ADCC, flow cytometry analysis, cytokine ELISA, and EGFR853-861 tetramer staining. Results: TLR8 stimulation of unfractionated PBMC led to enhanced cetuximab-mediated ADCC in healthy donors (p < 0.01) and HNC patients (p < 0.001), which was dependent on NK cells. Secretion of Th1 cytokines TNFα (p < 0.0001), IFNγ (p < 0.0001), and IL-12p40 (p < 0.005) was increased. TLR8 stimulation of PBMC augmented cetuximab-enhanced NK cell degranulation (p < 0.001). TLR8-stimulated NK cells enhanced DC maturation markers CD80, CD83, and CD86 in co-culture with cetuximab-treated HNC cells. TLR8 stimulation of NK-DC co-cultures significantly increased DC priming of EGFR-specific CD8+ T cells in the presence of cetuximab. Discussion: VTX-2337 and cetuximab combination therapy can activate innate and adaptive anti-cancer immune responses. Further investigation in human trials will be important for determining the clinical benefit of this combination and for determining biomarkers of response. © 2013 Springer-Verlag Berlin Heidelberg.

Zhang L.,University of Pittsburgh | Yu J.,University of Pittsburgh | Yu J.,Hillman Cancer Center Research Pavilion
Current Colorectal Cancer Reports | Year: 2013

Deregulation of apoptosis is a hallmark of human cancer and contributes to therapeutic resistance. Recent advances in cancer genomics have revealed a myriad of alterations in key pathways that directly or indirectly increase tumor cell survival. This review outlines the pathways of apoptosis in mammalian cells, and highlights the common alterations of apoptosis regulators found in colon cancer, the role of apoptosis, and underlying mechanisms in colon cancer treatment and prevention, including recent advances in investigational agents, such as kinase inhibitors, proteasome inhibitors, heat shock protein 90 inhibitors, BH3 mimetics, tumor necrosis factor related apoptosis-inducing ligand, and inhibitor of apoptosis protein antagonists. The topics also include novel concepts as well as opportunities and challenges for drug discovery and combination therapy by exploring cancerspecific genetic defects, and therefore selective induction of apoptosis in cancer cells. Although the emphasis is on colon cancer, the main theme and many of the aspects are applicable to other solid tumors. © Springer Science+Business Media New York 2013.

Horn C.C.,University of Pittsburgh | Horn C.C.,Hillman Cancer Center Research Pavilion
Experimental Brain Research | Year: 2014

Nausea and vomiting are ubiquitous as drug side effects and symptoms of disease; however, the systems that determine these responses are arguably designed for protection against food poisoning occurring at the level of the gastrointestinal (GI) tract. This basic biological pathway using GI vagal afferent communication to the brain is not well understood. Part of this lack of insight appears to be related to current experimental approaches, such as the use of experimental drugs, including systemic chemotherapy and brain penetrant agents, which activate parts of the nausea and vomiting system in potentially unnatural ways. Directly related to this issue is our ability to understand the link between nausea and vomiting, which are sometimes argued to be completely separate processes, with nausea as an unmeasurable response in animal models. An argument is made that nausea and emesis are the efferent limbs of a unified sensory input from the GI tract that is likely to be impossible to understand without more specific animal electrophysiological experimentation of vagal afferent signaling. The current paper provides a review on the use of animal models and approaches to defining the biological systems for nausea and emesis and presents a potentially testable theory on how these systems work in combination. © 2014 Springer-Verlag.

Zheng X.,University of Pittsburgh | He K.,University of Pittsburgh | Zhang L.,University of Pittsburgh | Yu J.,University of Pittsburgh | Yu J.,Hillman Cancer Center Research Pavilion
Molecular Cancer Therapeutics | Year: 2013

Oncogenic alterations in MET or anaplastic lymphoma kinase (ALK) have been identified in a variety of human cancers. Crizotinib (PF02341066) is a dual MET and ALK inhibitor and approved for the treatment of a subset of non-small cell lung carcinoma and in clinical development for other malignancies. Crizotinib can induce apoptosis in cancer cells, whereas the underlying mechanisms are not well understood. In this study, we found that crizotinib induces apoptosis in colon cancer cells through the BH3-only protein PUMA. In cells with wild-type p53, crizotinib induces rapid induction of PUMA and Bim accompanied by p53 stabilization and DNA damage response. The induction of PUMA and Bim is mediated largely by p53, and deficiency in PUMA or p53, but not Bim, blocks crizotinib-induced apoptosis. Interestingly, MET knockdown led to selective induction of PUMA, but not Bim or p53. Crizotinib also induced PUMA dependent apoptosis in p53-deficient colon cancer cells and synergized with gefitinib or sorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and therapeutic responses to crizotinib in xenograft models. These results establish a critical role of PUMA in mediating apoptotic responses of colon cancer cells to crizotinib and suggest that mechanisms of oncogenic addiction to MET/ALK-mediated survival may be cell type-specific. These findings have important implications for future clinical development of crizotinib. ©2013 American Association for Cancer Research.

He K.,University of Pittsburgh | Zheng X.,University of Pittsburgh | Zhang L.,University of Pittsburgh | Yu J.,University of Pittsburgh | Yu J.,Hillman Cancer Center Research Pavilion
Molecular Cancer Therapeutics | Year: 2013

Hsp90 is widely overexpressed in cancer cells and believed to be essential for the maintenance of malignant phenotypes. Targeting Hsp90 by small molecules has shown promise in solid and hematologic malignancies, which likely involves degradation of client oncoproteins in a cell-type-specific manner. In this study, we found that structurally unrelated Hsp90 inhibitors induce DNA damage and apoptosis via p53-dependent induction of PUMA, which indirectly triggers Bax activation and mitochondrial dysfunction in colon cancer cells. Deficiency in PUMA, BAX, or p53, at lesser extent, abrogated 17-allylamino-17-demethoxygeldanamycin (17-AAG)-induced apoptosis and mitochondrial dysfunction, and enhanced clonogenic cell survival. Furthermore, suppression of p53-dependent p21 induction or enhanced p53 activation synergized with 17-AAG to induce PUMA-dependent apoptosis. Finally, PUMA was found to mediate apoptotic and therapeutic responses to the 17-AAG analog 17-DMAG in xenografts. These results show an important role of the p53/PUMA/Bax axis in Hsp90 inhibitor-induced killing of p53 wild-type cells, and have important implications for their clinical applications. Mol Cancer Ther; 12(11); 2559-68. © 2013 AACR.

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