ADENOSINE IN TUMOR-HOST INTERACTION
Feoktistov Igor
Vanderbilt Universitycity: Nashville country: United States (us)
Grant 5R01CA138923-03 from National Cancer Institute
Keywords: Address; Adenine Nucleotides; Adenosine; Adenosine A2 Receptors; Adenosine A2A Receptor; Adenosine A2B Receptor; Adjuvant; Affinity; angiogenesis; Angiogenic Factor; Animals; Asthma; Attenuated; Blood Vessels; Bone Marrow; cancer immunotherapy; Cancer Vaccines; Cell Differentiation process; Cells; Characteristics; Clinical; Clinical Trials; cytokine; Data; Dendritic Cells; density; design; Development; Exhibits; extracellular; Foundations; Future; Hematopoietic; host neoplasm interaction; Hypoxia; Immune; Immune response; Immune Tolerance; Immunity; Immunotherapy; improved; In Vitro; in vivo; Inflammation; Isogenic transplantation; Knockout Mice; Malignant Neoplasms; Mediating; Mediator of activation protein; Modality; Modeling; mouse model; Mus; Myeloid Cells; Natural immunosuppression; Neoplasm Metastasis; novel therapeutics; Outcome; Phenotype; Production; Property; public health relevance; Purinergic P1 Receptors; receptor; Receptor Signaling; receptor-mediated signaling; Refractory; Regulation; research study; Resistance; Role; Shapes; Signal Transduction; Solid Neoplasm; Testing; Therapeutic; therapeutic target; Time; Treatment Efficacy; tumor; Tumor Angiogenesis; tumor growth; Tumor Immunity; Vascular Endothelial Growth Factors; Vascularization
Relevance: NARRATIVE The purpose of this study is to determine the role of adenosine signaling mediated via A2 adenosine receptor in aberrant differentiation and activation of tumor infiltrating myeloid cells, induction of immune suppression and tolerance and promoting tumor growth and vascularization. The important question of whether therapeutic blockage of A2 receptor signaling can produce improved clinical outcome and benefit anti-tumor immunity and whether adjuvant application of such therapy can enhance the efficacy of anti-angiogenic will be addressed. The anticipated data will lay the foundation for the future clinical trials of adenosine receptor antagonists and would have implications for the development of novel therapeutic modalities for cancer, anti-angiogenic and immunotherapies in particular
Project start date: 2010-07-07
Project end date: 2014-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
5R01CA138923-03 (2012): $317916
Sponsored Links Excellgen http://Excellgen.com
ADENOSINE IN TUMOR-HOST INTERACTION
Feoktistov Igor, Asst Professor
Vanderbilt Universitycity: Nashville country: United States (us)
Grant 5R01CA138923-02 from National Cancer Institute
Abstract: Metabolically stressful conditions, including inflammation and hypoxia characteristic of solid tumors, asthma and other pathological conditions, result in dramatic increases in extracellular concentrations of adenosine. Differentiation and functionality of immune cells critically depend on the microenvironment and under certain conditions tumor-infiltrating immune cells can benefit tumor by producing factors promoting angiogenesis and suppressing immunity. We have preliminary data demonstrating that stimulation of adenosine receptors skews dendritic cell (DC) differentiation from normal immune protective phenotype toward immune suppressive DC with pro-angiogenic and tumor-growth promoting properties. We also identified adenosine as an important metabolite inducing secretion of angiogenic factors including vascular endothelial growth factor (VEGF) by tumor immune infiltrate and identified A2B receptor as a mediator of the observed effects. The profound effect that signaling through A2B receptor has on differentiation and cytokine secretion by tumor infiltrating immune cells and tumor angiogenesis, identify A2B adenosine receptor as an important therapeutic target. Adenosine shapes tumor microenvironment through regulation the cytokine production by hematopoietic cells via both A2 (A2A and A2B) adenosine receptor-mediated signaling. Thus, we also propose the studies allowing to discriminate between the roles of A2A and A2B receptors in regulation the functions of tumor-infiltrating immune cells. We hypothesize that adenosine signaling through A2B receptor on host tumor-infiltrating immune cells benefits tumor growth and that therapeutic blockage of A2B and A2 receptor signaling will produce improved clinical outcome and benefit anti-tumor immunity. Using genetically modified and bone marrow chimeric mice, we intend to 1) Determine the functional significance of A2B and A2A/A2B receptor in cancer; 2) Determine whether A2 receptor-mediated VEGF production by hematopoietic cells benefits tumor growth and angiogenesis; 3) Determine the efficacy of therapy targeting A2B and A2 receptor signaling on tumor growth and vacularization, tumor-infiltrating immune cells, and immune responses. The anticipated data will lay the foundation for the future clinical trials of adenosine receptor antagonists and would have implications for the development of novel therapeutic modalities for cancer and immunotherapies. The purpose of this study is to determine the role of adenosine signaling mediated via A2 adenosine receptor in aberrant differentiation and activation of tumor infiltrating myeloid cells, induction of immune suppression and tolerance and promoting tumor growth and vascularization. The important question of whether therapeutic blockage of A2 receptor signaling can produce improved clinical outcome and benefit anti-tumor immunity and whether adjuvant application of such therapy can enhance the efficacy of anti-angiogenic will be addressed. The anticipated data will lay the foundation for the future clinical trials of adenosine receptor antagonists and would have implications for the development of novel therapeutic modalities for cancer, anti-angiogenic and immunotherapies in particular
Keywords: Address; Adenine Nucleotides; Adenosine; Adenosine A(2A) Receptor; Adenosine A(2B) Receptor; Adenosine A2 Receptors; Adenosine A2A Receptor; Adenosine A2B Receptor; Adenosine Phosphates; Adjuvant; Affinity; angiogenesis; Angiogenic Factor; Animals; Antineoplastic Vaccine; Asthma; Attenuated; biological signal transduction; Blood Vessels; Bone Marrow; Bronchial Asthma; cancer immunotherapy; cancer metastasis; Cancer Vaccines; Cancers; Cell Communication and Signaling; Cell Differentiation; Cell Differentiation process; Cell Signaling; Cells; Characteristics; Clinical; clinical investigation; Clinical Trials; Clinical Trials, Unspecified; cytokine; Data; Dendritic Cells; density; design; designing; Development; Exhibits; experiment; experimental research; experimental study; extracellular; Factor, Angiogenesis; Foundations; Future; Hematopoietic; Homograft, Isogeneic; Homograft, Syngeneic; host neoplasm interaction; host response; Host-Tumor Interaction; Hypoxia; Hypoxic; Immune; Immune response; immune system tolerance; immune therapy; Immune Tolerance; immune unresponsiveness; Immunity; Immuno-Chemotherapy; Immunochemotherapy; Immunologic Tolerance; immunological paralysis; Immunologically Directed Therapy; immunoresponse; immunosuppression; Immunosuppression Effect; Immunosuppressions (Physiology); Immunosuppressive Effect; Immunotherapy; Immunotherapy, Cancer, General; improved; In Vitro; in vivo; Inflammation; INFLM; Intracellular Communication and Signaling; Isogenic transplantation; Isograft; ITX; Knockout Mice; malignancy; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; Mice; Mice, Knock-out; Mice, Knockout; Modality; Modeling; mouse model; Murine; Mus; Myeloid Cells; Natural immunosuppression; Neoplasm Metastasis; neoplasm/cancer; new therapeutics; next generation therapeutics; novel therapeutics; Null Mouse; Outcome; Oxygen Deficiency; P1 Purinoceptors; Phenotype; Production; Property; Property, LOINC Axis 2; public health relevance; Purinergic P1 Receptors; receptor; Receptor Protein; Receptor Signaling; receptor-mediated signaling; Receptors, Adenosine; Receptors, Purinergic P1; Refractory; Regulation; research study; Resistance; resistant; Reticuloendothelial System, Bone Marrow; Role; Secondary Neoplasm; Secondary Tumor; Shapes; Signal Transduction; Signal Transduction Systems; Signaling; social role; Solid Neoplasm; Solid Tumor; Testing; Therapeutic; therapeutic efficacy; therapeutic target; therapeutically effective; Time; Transplantation, Isogeneic; Transplantation, Syngeneic; Treatment Efficacy; tumor; Tumor Angiogenesis; Tumor Cell Migration; tumor growth; Tumor Immunity; Vaccines, Neoplasm; Vaccines, Tumor; vascular; Vascular Endothelial Growth Factors; Vascularization; Vegf; VEGFs; Veiled Cells
Relevance: NARRATIVE The purpose of this study is to determine the role of adenosine signaling mediated via A2 adenosine receptor in aberrant differentiation and activation of tumor infiltrating myeloid cells, induction of immune suppression and tolerance and promoting tumor growth and vascularization. The important question of whether therapeutic blockage of A2 receptor signaling can produce improved clinical outcome and benefit anti-tumor immunity and whether adjuvant application of such therapy can enhance the efficacy of anti-angiogenic will be addressed. The anticipated data will lay the foundation for the future clinical trials of adenosine receptor antagonists and would have implications for the development of novel therapeutic modalities for cancer, anti-angiogenic and immunotherapies in particular
Project start date: 2010-07-07
Project end date: 2015-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01CA138923-02 (2011): $326696