ROLE OF IMMUNITY IN EFFICACY OF CHEMOTHERAPY PLUS TRASTUZUMAB
L Keith, Deputy Director
Mayo Clinic Jacksonvillecity: Jacksonville country: United States (us)
Grant 1R01CA152045-01A1 from National Cancer Institute
Abstract: The primary objectives of this proposal examine immunologic mechanisms of anti-HER2 therapies. The general hypothesis is that trastuzumab, when combined with chemotherapy, actively immunizes patients leading to the generation of adaptive immune effector cells or antibodies that are associated with therapeutic efficacy. Immune effectors generated at tumor sites and regional lymph nodes and released into blood may be potential biomarkers of trastuzumab response. Trastuzumab has in part an immunologic mechanism of action, and preliminary results from Dr. Knutson and Dr Clynes suggest that an adaptive immune response is responsible for the clinical actions of trastuzumab. An advantage of immune biomarkers is that a simple blood draw may suffice for detection. Our specific aims include 1) To determine whether anti-HER2 antibody responses, generated during chemotherapy and trastuzumab in breast cancer patients, are associated with clinical responses. We will perform retrospective analyses of endogenous HER2-specific antibody responses using serum samples collected from metastatic breast cancer patients treated with chemotherapy and trastuzumab; 2) To determine whether a HER2-specific T cell immune response is induced in HER2+ breast cancer patients treated with chemotherapy and trastuzumab. We will perform a prospective study evaluating T cell and antibody immunity in adjuvant and metastatic breast cancer patients treated with chemotherapy and trastuzumab; 3) To determine whether the improved disease-free survival and overall survival in patients treated in the adjuvant setting with combination of chemotherapy and trastuzumab is associated with the Fc? receptor genotype of the patient. HER2-positive breast cancers are very aggressive and account for 15-20% of all breast cancer cases. Trastuzumab, an antibody against the HER2 protein, has revolutionized the treatment for these cancers, but not all HER2-positive patients respond to trastuzumab and therefore, additional tissue and blood tests that can better predict the response to trastuzumab are needed to more effectively personalize therapy. We propose to evaluate blood immune cells as indicators of trastuzumab response that may help identify those patients most likely to benefit from trastuzumab
Keywords: Accounting; ADCC; Adjuvant; Affinity; Anti-c-ERB-2; Anti-c-erbB2 Monoclonal Antibody; Anti-ERB-2; Anti-erbB-2; Anti-erbB2 Monoclonal Antibody; Anti-HER2/c-erbB2 Monoclonal Antibody; Anti-p185-HER2; Antibodies; Antibody -dependent cell cytotoxicity; antibody biosynthesis; antibody dependent cell mediated cytotoxicity; Antibody Formation; Antibody Production; antibody receptor; Antibody Response; Antibody-Dependent Cellular Cytotoxicity; anticancer therapy; Antigenic Determinants; B blood cells; B-Cells; B-Lymphocytes; base; Binding; Binding (Molecular Function); Binding Determinants; Biology; biomarker; Blood; Blood Serum; Blood Tests; Body Tissues; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; c-erb-2 Monoclonal Antibody; c-erbB-2; c-erbB-2 Genes; c-erbB-2 Proto-Oncogenes; Cancer of Breast; Cancer Patient; cancer therapy; Cancer Treatment; Cancers; Cause of Death; CD4 lymphocyte; CD4 Positive T Lymphocytes; CD4 T cells; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD8; CD8B; CD8B1; CD8B1 gene; Cell Cytoxicity, Antibody-Dependent; Cell-Mediated Lympholytic Cells; Cells; Cells, CD4; chemotherapy; Clinic; Clinical; clinical efficacy; clinical investigation; Clinical Trials; Clinical Trials, Unspecified; cohort; Combination Drug Therapy; combination pharmacotherapy; combination therapy; Combined Modality Therapy; combined modality treatment; combined treatment; Common Neoplasm; Common Tumor; CTL; Cytolytic T-Cell; cytotoxic; Cytotoxic cell; Cytotoxic T Cell; Cytotoxic T-Lymphocytes; Deoxyribonucleic Acid; Detection; Development; Disease; Disease Progression; Disease-Free Survival; disease/disorder; Disorder; DNA; Effectiveness; Effector Cell; Epitopes; Epitopes, T-Lymphocyte; ERBB2; ERBB2 gene; Event-Free Survival; External Domain; Extracellular Domain; Family; Fc Receptor; FcR; gene product; Generations; Genes; Genes, erbB-2; Genes, HER-2; Genes, HER2; Genes, neu; Genotype; heavy metal lead; heavy metal Pb; helper T cell; Hematologic Tests; Hematological Tests; Hematology Testing; HER -2; HER-2; HER2; HER2 Monoclonal Antibody; HER2/neu; HLA-BR; HLA-BR Antigens; HLA-D-Related Antigens; HLA-DR; HLA-DR Antigens; HLA-MT; HLA-MT Antigens; host response; Human EGF Receptor 2 Gene; human IGFBP2 protein; humanized monoclonal antibodies; IBP-2; IGF-Binding Protein 2; IGF-BP53; IGFBP-2; IGFBP2 protein, human; Immune; Immune response; immune therapy; Immunity; immunoglobulin biosynthesis; Immunologic, Immunochemical; Immunologically Directed Therapy; Immunologics; immunoresponse; Immunotherapy; improved; insight; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 2 (36kD); Insulin-Like Growth Factor Binding Protein 2, 36kDa; interest; ITX; K lymphocyte; Lead; lymph gland; Lymph node proper; lymph nodes; LYT3; malignancy; malignant breast neoplasm; Malignant neoplasm of breast; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Breast; Measures; Mediating; MoAb HER2; Molecular; Molecular Interaction; multidisciplinary; Multimodal Therapy; Multimodal Treatment; multimodality therapy; Multimodality Treatment; Natural Killer Cells; NCCTG; neoplasm/cancer; neoplastic cell; NK Cells; North Central Cancer Treatment Group; Outcome; overexpression; Pathogenesis; pathway; Pathway interactions; Patient Selection; Patients; Pb element; Polychemotherapy; Progression-Free Survivals; Prospective Studies; Proteins; public health relevance; receptor; Receptor Protein; Research; Resistance; resistance to therapy; resistant; resistant to therapy; response; Reticuloendothelial System, Blood; Reticuloendothelial System, Lymph Node; rhuMAb HER2; Role; Sampling; Serum; Site; social role; Staging; T-Cell Epitopes; T-Cells; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocytes, Cytotoxic; T4 Cells; T4 Lymphocytes; Testing; therapeutic efficacy; therapeutically effective; therapy resistant; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; Tissues; TKR1; Trastuzumab; Treatment Efficacy; tumor; Tumor Antigens; Tumor Burden; Tumor Cell; Tumor Load; Tumor-Associated Antigen; tumor-specific antigen; Woman
Relevance: HER2-positive breast cancers are very aggressive and account for 15-20% of all breast cancer cases. Trastuzumab, an antibody against the HER2 protein, has revolutionized the treatment for these cancers, but not all HER2-positive patients respond to trastuzumab and therefore, additional tissue and blood tests that can better predict the response to trastuzumab are needed to more effectively personalize therapy. We propose to evaluate blood immune cells as indicators of trastuzumab response that may help identify those patients most likely to benefit from trastuzumab
Project start date: 2011-01-01
Project end date: 2015-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-10-067
1R01CA152045-01A1 (2011): $619306
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to L Keith
T-COHR: TRAINING IN CRANIOFACIAL AND ORAL HEALTH RESEARCH
L Keith, Associate Dean For Research
Medical University Of South Carolinacity: Charleston country: United States (us)
Grant 2T32DE017551-06 from National Institute Of Dental & Craniofacial Research
Abstract: This is a competing renewal application for a T32 grant that supports Training in Craniofacial and Oral Health Research (T-COHR), an integrated research training program based in the College of Dental Medicine at the Medical University of South Carolina (MUSC). The overarching objective of T-COHR is to foster the development of clinician scientists and scientists focused on oral, dental and craniofacial research. T-COHR provides a strong curriculum and thematic research experiences in an integrative framework that emphasizes mentoring, scientific advancement, academic career development, grantsmanship and productivity. This application requests (1) continued support for the Dental Scientist Training Program (DSTP), offering a consolidated DMD/PhD degree pathway; (2) continued support for predoctoral research training leading to the PhD degree in biomedical sciences or bioengineering with applications to oral/craniofacial health; and (3) continued support for postdoctoral research training for dentist-scientists and/or non-clinician PhD scientists in basic, translational or bioengineering sciences important to dental, oral or craniofacial health. T-COHR is an integral part of the Center for Oral Health Research (COHR), a University Center of Research Excellence in the College of Dental Medicine that engages faculty and trainees in other disciplines and departments in the Colleges of Medicine, Graduate Studies, Nursing and Dental Medicine at MUSC, the Department of Bioengineering at Clemson University, and the Hollings Cancer Center at MUSC. T-COHR mentoring and training activities are thematically grouped in 4 strategic areas of research focus (i) basic and translational science related to oral infection and inflammation, (ii) oral pharyngeal cancer biology and cancer immunology, (iii) bioengineering/biomechanics and craniofacial regeneration, and (iv) bio-behavioral factors related to oral and systemic health in special populations. Integrative activities include a College of Medicine Scholars Day, COHR Monthly Meetings and Symposia, an Oral Health Journal Club and Oral Health Seminar Series, as well as didactic instruction through courses designed specifically for T-COHR trainees. T-COHR benefits from excellent administrative support and institutional commitment that provide sustainability to the Center for Oral Health Research. T-COHR includes an integrated multi-year evaluation plan to measure the extent to which program goals and objectives are met. In the United States, there remains a critical need for well-trained investigators in dental, oral and craniofacial research. This training grant application supports Training in Craniofacial and Oral Health Research (T-COHR), an integrated program based in the College of Dental Medicine at the Medical University of South Carolina (MUSC) to help train the next generation of clinician scientists and scientists engaged in dental, oral and craniofacial research. Research training will be in the areas of oral infection and inflammation, oral cancer, bioengineering and craniofacial regeneration, and bio-behavioral factors related to oral health in special populations
Keywords: craniofacial; Oral health; Research; Training
Relevance: In the United States, there remains a critical need for well-trained investigators in dental, oral and craniofacial research. This training grant application supports Training in Craniofacial and Oral Health Research (T-COHR), an integrated program based in the College of Dental Medicine at the Medical University of South Carolina (MUSC) to help train the next generation of clinician scientists and scientists engaged in dental, oral and craniofacial research. Research training will be in the areas of oral infection and inflammation, oral cancer, bioengineering and craniofacial regeneration, and bio-behavioral factors related to oral health in special populations
Project start date: 2006-07-01
Project end date: 2016-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PAR-10-171
2T32DE017551-06 (2011): $530113
SOUTH CAROLINA COBRE FOR ORAL HEALTH RESEARCH
L Keith, Associate Dean For Research
Medical University Of South Carolinacity: Charleston country: United States (us)
Grant 5P20RR017696-10 from National Center For Research Resources
Abstract: This application from the College of Dental Medicine (COM) at the Medical University of South Carolina (MUSC) requests renewal of the COBRE for Oral Health. The initial COBRE award in 2002 had a catalytic impact on the development of research capacity in MUSC´s College of Dental Medicine and dramatically enlightened awareness of and interest in oral and craniofacial research campus-wide. The overall objective of this proposal is to firmly establish the MUSC Center for Oral Health Research (COHR) as a sustainable, independent multidisciplinary research center. Continued funding through the NCRR COBRE Program will ensure that the momentum gained during the first cycle will be unabated and the trajectory of research competitiveness will continue to climb in terms of both individual investigator awards and multi-investigator mechanisms such as program projects, center grants and additional training grants. In this renewal proposal we are requesting support for five junior investigators (four currently at MUSC and one to be recruited), who will conduct research projects of their own design with substantial one on- one and team mentoring, as well as two critical scientific cores and an administrative core that includes proven components for management and oversight, faculty development and program planning. The specific aims for the COBRE renewal are AIM 1 Expand the critical mass of funded investigators in oral and craniofacial research by a. mentoring the research career development of 5 to 6 additional outstanding new targeted investigators with interests and talents relevant to our theme, and b. enhancing the long-term development and continuing success of graduates as independent investigators. AIM 2 Enhance scientific core resources that will serve as platforms to increase the capacity of our targeted faculty to compete successfully for NIH funding. AIM 3 Fully implement the MUSC Center for Oral Health Research as the vehicle for successful transition to long-term competitive, renewable support from a diverse range of federal and non-federal sources
Project start date: 2002-09-30
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-RR-06-001
5P20RR017696-10 (2011): $2125614
POST-TRANSCRIPTIONAL REGULATION OF PERIODONTAL DISE
L Keith, Associate Dean For Research
Medical University Of South Carolinacity: Charleston country: United States (us)
Grant 1R01DE021423-01A1 from National Institute Of Dental & Craniofacial Research
Abstract: Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. Tristetraprolin (TTP) is a zinc finger protein that binds to the ARE of cytokine mRNAs and enhances degradation of the mRNA. TTP is phosphorylated by the p38-MK2 pathway and may serve as a general mechanism of cytokine mRNA regulation. The objective of this application is to determine how TTP and the MK2 pathway modify periodontal disease initiation and progression. Experimental models of periodontitis where TTP is over-expressed show a reduction of pro-inflammatory proteins and reduced amount of LPS-induced alveolar bone loss. Preliminary data for this proposal indicates that mutant mice lacking TTP display an increased amount of periodontal bone loss compared with wild type littermates. The aims for this proposal are 1) to determine the role of TTP expression/phosphorylation status directs local inflammatory cytokine expression in periodontal disease progression, 2) to determine if TTP will determine the extent of inflammation and alveolar bone loss in experimental models of periodontal disease, and 3) measure TTP expression and phosphorylation status in human periodontal disease progression. These studies will establish the role of a key RNA binding protein in experimental models and human periodontitis. Using genetic models lacking TTP or the key kinase that modulates TTP function, MK2, definitive data relative to TTP biology related to periodontal disease will be gained. Foundation and translational significance of mRNA stability will provide insight into the potential of these proteins to be targeted for future studies that will modify innate immune cytokine expression for therapeutic benefit in the management of chronic periodontitis. Periodontal disease progression occurs as a consequence of the host immune inflammatory response to oral pathogens. These studies will establish the role of RNA binding proteins needed to mediate inflammatory cytokine mRNA stability. Progress in understanding the role of posttranscriptional cytokine regulation in periodontal inflammation and bone loss may yield new possibilities for treatment of periodontal diseases
Keywords: 3` Untranslated Regions; Abbreviations; Acid Phosphatase; Actinobacillus actinomycetemcomitans; Address; Adenosine; Alveolar Bone Loss; Binding Proteins; Biology; bone; bone loss; BRF1 gene; butyrate response factor 1; Clinical; collagenase 3; cyclooxygenase 2; cytokine; Data; Dinoprostone; Disease; Disease Progression; DUSP1 gene; Elements; Excision; Experimental Models; Extracellular Signal Regulated Kinases; Foundations; Future; Gene Expression; Genetic Models; Germ-Free; Goals; Green Fluorescent Proteins; Human; Immune; Immunohistochemistry; in vivo; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; insight; Interleukin-6; Interleukins; Lipopolysaccharides; MAP Kinase Gene; MAPK phosphatase; MAPK14 gene; MAPK8 gene; Measures; Mediating; Membrane; Messenger RNA; Mitogen-Activated Protein Kinases; Modeling; mRNA Decay; mRNA Stability; mRNA Transcript Degradation; Mus; Mutant Strains Mice; NF-kappa B; Operative Surgical Procedures; Oral; oral pathogen; Organism; pathogen; Pathogenesis; pathogenic bacteria; Pathway interactions; Periodontal Diseases; Periodontitis; Phosphorylation; Phosphotransferases; Play; Post-Transcriptional Regulation; Process; Production; Protein Binding; protein complex; Protein Kinase; Proteins; PTGS2 gene; receptor; Regulation; Relative (related person); research study; Resistance; RNA-Binding Proteins; Role; Specimen; stress-activated protein kinase 1; Testing; Therapeutic; Time; TIS11 protein; Tissues; TNF gene; TNFSF11 gene; Tumor Necrosis Factor-alpha; Uridine; X-Ray Computed Tomography; Zinc Fingers
Relevance: Periodontal disease progression occurs as a consequence of the host immune inflammatory response to oral pathogens. These studies will establish the role of RNA binding proteins needed to mediate inflammatory cytokine mRNA stability. Progress in understanding the role of posttranscriptional cytokine regulation in periodontal inflammation and bone loss may yield new possibilities for treatment of periodontal diseases
Project start date: 2011-07-01
Project end date: 2016-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-067
1R01DE021423-01A1 (2011): $368750
NEGATIVE REGULATION OF INNATE IMMUNE RESPONSES THROUGH MAPK PHOSPHATASES
L Keith, Associate Dean For Research
Medical University Of South Carolinacity: Charleston country: United States (us)
Grant 5R01DE018290-06 from National Institute Of Dental & Craniofacial Research
Abstract: Periodontal disease initiation and progression occurs as a consequence of the host immune inflammatory response to oral pathogens. The production of inflammatory cytokines is a highly regulated process involving transcriptional and posttranscriptional mechanisms. One of the major signaling pathways activated by periopathogenic LPS in p38 MARK. Following p38 phosphorylation, inactivation of p38 MAP kinases is achieved mainly by a family of dual-specific MAP kinase phosphatases (MKP). MKP-1 is capable of negatively regulating both transcriptional and post transcriptional p38 MAP kinase activity. MKP-1 contributes towards LPS tolerance and over-expression of MKP-1 has shown to accelerate p38 inactivation resulting in diminished proinflammatory cytokine production. We have recently shown that LPS-induced IL-6 mRNA stability expression requires p38 signaling. Preliminary data for this proposal indicates that in MKP- 1 transfected cells, LPS-induced IL-6 expression is significantly attenuated. In addition, we have provided significant data showing the p38 is a major signaling pathway contributing to LPS-induced periodontal bone destruction. Based upon these data, we hypothesize that the endogenous negative regulator mechanism of p38 signaling, MKP-1, is a key component of responsible for attenuation of LPS-induced inflammatory cytokine expression in macrophages. In this proposal, the ability of TIP over-expression to decrease inflammation will be determined in vitro using gene targeted strategies in macrophages, and in vivo using experimental periodontitis models. The specific aims are 1) To determine the role of over-expressed MKP-1 on IL-6 and TNFa mRNA expression in vitro. 2) To determine the contribution of MKP-1 in ontogeny of inflammatory cytokine production and LPS-induced osteoclastogenesis in primary bone marrow macrophages and 3) To determine the impact of MKP-1 in inflammatory bone destruction in vivo using MKP mice. These studies will establish the role of LPS-induced cytokine expression and negative regulation in inflammatory bone loss through selective attenuation of p38 MAPK-induced signaling in periodontal bone destruction
Keywords: 21+ years old; 3` Untranslated Regions; 3`UTR; A. actinomycetemcomitans; Abbreviations; Acid Phosphatase; Actinobacillus actinomycetemcomitans; Acute; Address; Adenosine; Adult; adult human (21+); Alveolar Bone Loss; Alveolar Resorption; Assay; ATP-protein phosphotransferase; Attenuated; attenuation; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; Bacterium actinomycetem comitans; Bacterium comitans; base; BCDF; Binding Proteins; Bioassay; Biologic Assays; Biological Assay; biological signal transduction; Body Tissues; bone; Bone; Bone and Bones; bone loss; Bone Marrow; Bones and Bone Tissue; BRF Gene; BRF1; BRF1 gene; BRF2; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); butyrate response factor 1; Butyrate Response Factor 2; butyrate response factor 2 protein, human; c-jun Amino-Terminal Kinase; c-jun Kinase-1; c-jun N-Terminal Kinase; c-jun N-Terminal Kinase 1; Cachectin; Cachectin-Tumor Necrosis Factor; CAT scan; CAT Scan, X-Ray; catscan; Cell Communication and Signaling; Cell Signaling; Cell/Tissue, Immunohistochemistry; Cells; Chronic; Chronic Periodontitis; cMG1 protein; collagenase 3; Common Rat Strains; computed axial tomography; Computed Tomography; computerized axial tomography; Computerized Axial Tomography (Computerized Tomography); computerized tomography; Computerized Tomography, X-Ray; COX-2; COX-2 protein; COX2; COX2 enzyme; CSBP1; CSBP2; CSPB1; CT scan; CT X Ray; cyclo-oxygenase II; Cyclo-Oxygenase-2; Cyclooxygenase; cyclooxygenase 2; cytokine; Cytokines and Inflammatory Response; Data; Development; DIF; Differentiation Factor, B-Cell; Dinoprostone; Disease; Disease Progression; disease/disorder; Disorder; EC 2.7; EC 2.7.2-; EGF-Response Factor 2; EGF-response factor 2 protein, human; Elements; EMI scan; ERF-2 Protein; ERF-2 protein, human; ERF2; ERK MAP Kinases; EXIP; Experimental Models; Experimental Models, Other; Extracellular Signal Regulated Kinases; extracellular signal related kinase; Extracellular Signal-Regulated Kinase Gene; Extracellular Signal-Regulated Kinases; Extracellular Signal-Regulated MAP Kinases; Family; fetal; G0-G1 switch regulatory protein 24; Gene Targeting; General Transcription Factor 3B, 90-kD Subunit; Generalized Growth; GFP; glycogen synthase a kinase; GM-CSF; GMCSF; Goals; GOS24 protein; granulocyte macrophage colony stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor; Green Fluorescent Proteins; Growth; hCOX-2; Hepatocyte-Stimulating Factor; Histamine-Producing Cell-Stimulating Factor; host response; HPGF; hRANKL2; human ZFP36L2 protein; Human, Adult; Hybridoma Growth Factor; hydroxyalkyl protein kinase; IFN-beta 2; IFNB2; IHC; IL-6; IL6 Protein; Immune; Immune response; Immunoglobulin Enhancer-Binding Protein; Immunohistochemistry; Immunohistochemistry Staining Method; immunoresponse; In Vitro; in vivo; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; INFLM; interferon beta 2; Interleukin 6 (Interferon, Beta 2); Interleukin-6; Interleukins; Intracellular Communication and Signaling; Investigators; JN Kinase; JNK; JNK Mitogen-Activated Protein Kinases; JNK1; JNK1 Kinase; JNK1 protein; JNK1A2; JNK21B1/2; jun-NH2-Terminal Kinase; kappa B Enhancer Binding Protein; Kinases; Ligand Binding Protein; Lipopolysaccharides; living system; LPS; macrophage; Mammals, Mice; Mammals, Rats; MAP kinase; MAP Kinase 8; MAP Kinase 8 Gene; MAP Kinase Gene; MAPK; MAPK phosphatase; MAPK14; MAPK14 gene; MAPK8; MAPK8 gene; MAPK8 Mitogen-Activated Protein Kinase; MAPKAPK-2; MAPKAPK2; matrix metalloproteinase-13; MGI-2; Mice; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinase Gene; mitogen-activated protein kinase p38; Mitogen-Activated Protein Kinases; MMP-13; MMP-13 gene product; MMP13 gene product; Modeling; Models, Experimental; Molecular; Molgramostin; mRNA Expression; mRNA Stability; Murine; Mus; Mxi2; Myeloid Differentiation-Inducing Protein; Nature; NF-kappa B; NF-kappaB; NF-kB; NFKB; Nuclear Factor kappa B; nuclear factor kappa beta; Nuclear Transcription Factor NF-kB; NuP475 protein; ODF; ontogeny; OPGL; Oral; oral pathogen; Organism; Orthophosphoric-monoester phosphohydrolase (acid optimum); osteoclastogenesis; Osteoclasts; p38; p38 MAP Kinase; p38 MAPK; p38 MAPK Gene; p38 Protein Kinase; p38 SAPK; p38Alpha; Parodontosis; pathogen; pathway; Pathway interactions; Periodontal Bone Loss; Periodontal Diseases; periodontal disorder; Periodontal Resorption; Periodontitis; periodontium disease; periodontium disorder; PGE2; PGE2 alpha; PGE2alpha; PGG/HS; PGH Synthase 2; PGHS-2; PGHS2; Phosphatases; Phosphohydrolases; Phosphomonoesterases; Phosphoric Monoester Hydrolases; phosphorylase b kinase kinase; Phosphorylation; Phosphotransferases; PHS II; PHS-2; Plasmacytoma Growth Factor; Play; PRKM14; PRKM15; PRKM8; Process; Production; programs; Programs (PT); Programs [Publication Type]; Prosta-5, 13-dien-1-oic acid, 11, 15-dihydroxy-9-oxo-, (5Z, 11alpha, 13E, 15S)-; Prostaglandin E2; Prostaglandin E2 alpha; Prostaglandin E2alpha; Prostaglandin G/H Synthase 2; Prostaglandin G/H Synthase and Cyclooxygenase; prostaglandin H synthase-2; Prostaglandin H2 Synthase 2; Prostaglandin-Endoperoxide Synthase 2; Protein Kinase; Protein Phosphorylation; prototype; PTGS2; PTGS2 gene; RANKL; Rat; Rattus; receptor; Receptor Protein; Regulation; Research Personnel; Researchers; Resistance; resistant; response; Reticuloendothelial System, Bone Marrow; Role; SAP Kinase-1; SAPK/JNK; SAPK1; SAPK1 Mitogen-Activated Protein Kinase; SAPK1/JNK; SAPK2A; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Site; social role; sOdf; Stress; stress-activated protein kinase 1; Stress-Activated Protein Kinase gamma; Stress-Activated Protein Kinase JNK1; System; System, LOINC Axis 4; TAF3B2 Gene; TAF3C, Formerly; Targetings, Gene; TC-GM-CSF; TFIIIB90 Gene; Threonine/Tyrosine Protein Kinase; TIS11 protein; TIS11b protein; TIS11D; TIS11D Protein; Tissue Growth; Tissues; TLR protein; TNF; TNF (unspecified); TNF A; TNF gene; TNF Receptor Ligands; TNF-alpha; TNFSF11; TNFSF11 gene; TNFSF2; Toll-like receptors; Tomodensitometry; Tomography, Xray Computed; Transcription Factor NF-kB; Transphosphorylases; tristetraprolin; TTP protein; Tumor Necrosis Factor; tumor necrosis factor (unspecified); Tumor Necrosis Factor Family Protein; Tumor Necrosis Factor Gene; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor-Cell Human GM Colony-Stimulating Factor; unspecified interleukin; Urd; Uridine; Wild Type Mouse; X-Ray Computed Tomography; ZFP36 protein; ZFP36L2; ZFP36L2 gene; ZFP36L2 protein, human; Zinc Finger Protein 36 C3H Type-Like 2; zinc finger protein 36, C3H type-like 2 protein, human
Project start date: 2007-02-07
Project end date: 2012-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: RFA-DE-07-004
5R01DE018290-06 (2011): $298947
ROLE OF IMMUNITY IN EFFICACY OF CHEMOTHERAPY PLUS TRASTUZUMAB
L Keith
Mayo Clinic Jacksonvillecity: Jacksonville country: United States (us)
Grant 5R01CA152045-02 from National Cancer Institute
Keywords: Accounting; Adjuvant; Affinity; Antibodies; Antibody -dependent cell cytotoxicity; Antibody Formation; B-Lymphocytes; base; Binding (Molecular Function); Biology; biomarker; Blood; Blood Tests; Cancer Patient; cancer therapy; Cause of Death; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; chemotherapy; Clinic; Clinical; clinical efficacy; Clinical Trials; cohort; Combination Drug Therapy; Combined Modality Therapy; Common Neoplasm; cytotoxic; Cytotoxic T-Lymphocytes; Detection; Development; Disease; Disease Progression; Disease-Free Survival; DNA; Effectiveness; Effector Cell; Epitopes; ERBB2 gene; Extracellular Domain; Family; Fc Receptor; Generations; Genes; Genotype; HLA-DR Antigens; human IGFBP2 protein; humanized monoclonal antibodies; Immune; Immune response; Immunity; Immunologics; Immunotherapy; improved; insight; interest; Lead; lymph nodes; malignant breast neoplasm; Malignant Neoplasms; Measures; Mediating; Molecular; multidisciplinary; Natural Killer Cells; neoplastic cell; North Central Cancer Treatment Group; Outcome; overexpression; Pathogenesis; Pathway interactions; Patient Selection; Patients; Progression-Free Survivals; Prospective Studies; Proteins; public health relevance; receptor; Research; Resistance; response; Role; Sampling; Serum; Site; Staging; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; therapy resistant; Tissues; Trastuzumab; Treatment Efficacy; tumor; Tumor Antigens; Tumor Burden; Woman
Relevance: HER2-positive breast cancers are very aggressive and account for 15-20% of all breast cancer cases. Trastuzumab, an antibody against the HER2 protein, has revolutionized the treatment for these cancers, but not all HER2-positive patients respond to trastuzumab and therefore, additional tissue and blood tests that can better predict the response to trastuzumab are needed to more effectively personalize therapy. We propose to evaluate blood immune cells as indicators of trastuzumab response that may help identify those patients most likely to benefit from trastuzumab
Project start date: 2011-01-01
Project end date: 2015-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
5R01CA152045-02 (2012): $503660