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1.
Oncotarget ; 8(66): 109973-109984, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-29299123

RESUMO

Resistance to targeted tyrosine kinase inhibitors (TKI) remains a challenge for the treatment of myeloid leukemias. Following treatment with TKIs, the bone marrow microenvironment has been found to harbor a small pool of surviving leukemic CD34+ progenitor cells. The long-term survival of these leukemic cells has been attributed, at least in part, to the protective effects of bone marrow stroma. We found that the NOX-A12 'Spiegelmer', an L-enantiomeric RNA oligonucleotide that inhibits SDF-1α, showed in vitro and in vivo activity against BCR-ABL- and FLT3-ITD-dependent leukemia cells. NOX-A12 was sufficient to suppress SDF-1-induced migration in vitro. The combination of NOX-A12 with TKIs reduced cell migration in the same in vitro model of SDF-1-induced chemotaxis to a greater extent than either drug alone, suggesting positive cooperativity as a result of the SDF-1 blocking function of NOX-A12 and cytotoxicity resulting from targeted oncogenic kinase inhibition. These results are consistent with our in vivo findings using a functional pre-clinical mouse model of chronic myeloid leukemia (CML), whereby we demonstrated the ability of NOX-A12, combined with the ABL kinase inhibitor, nilotinib, to reduce the leukemia burden in mice to a greater extent than either agent alone. Overall, the data support the idea of using SDF-1 inhibition in combination with targeted kinase inhibition to override drug resistance in oncogene-driven leukemia to significantly diminish or eradicate residual leukemic disease.

2.
Stem Cell Rev Rep ; 13(2): 278-286, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27924617

RESUMO

Mobilized bone marrow-derived stem cells (BMSC) have been discussed as an alternative strategy for endogenous repair. Thereby, different approaches for BMSC mobilization have been pursued. Herein, the role of a newly discovered oligonucleotide for retinal homing and regeneration capability of BMSCs was investigated in the sodium iodate (NaIO3) model of retinal degeneration. Mobilization was achieved in GFP-chimera with NOX-A12, a CXC-motif chemokine ligand 12 (CXCL12)/stromal cell-derived factor 1 (SDF-1)-neutralizing L-aptamer. BMSC homing was directed by intravitreal SDF-1 injection. Visual acuity was measured using the optokinetic reflex. Paraffin cross sections were stained with hematoxylin and eosin for retinal thickness measurements. Immunohistochemistry was performed to investigate the expression of cell-specific markers after mobilization. A single dose of NOX-A12 induced significant mobilization of GFP+ cells which were found in all layers within the degenerating retina. An additional intravitreal injection of SDF-1 increased migration towards the site of injury. Thereby, the number of BMSCs (Sca-1+) found in the damaged retina increased whereas a decrease of activated microglia (Iba-1+) was found. The mobilization led to significantly increased visual acuity. However, no significant changes in retinal thickness or differentiation towards retinal cell types were detected. Systemic mobilization by a single dose of NOX-A12 showed increased homing of BMSCs into the degenerated retina, which was associated with improved visual function when injection of SDF-1 was additionally performed. The redistribution of the cells to the site of injury combined with their observed beneficial effects support the endogenous therapeutic strategy for retinal repair.


Assuntos
Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Degeneração Retiniana/prevenção & controle , Animais , Aptâmeros de Nucleotídeos , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Quimiocina CXCL12/administração & dosagem , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Imuno-Histoquímica , Injeções Intraoculares , Iodatos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Retina/citologia , Degeneração Retiniana/induzido quimicamente , Degeneração Retiniana/fisiopatologia , Tubulina (Proteína)/metabolismo , Acuidade Visual/efeitos dos fármacos
3.
Oncotarget ; 6(14): 12048-60, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25895128

RESUMO

Homing to distinct lymphoid organs enables chronic lymphocytic leukemia (CLL) cells to receive pro-survival and proliferative signals. Cytogenetic aberrations can significantly affect CLL cell compartmentalization. Trisomy 12 (tri12) defines a CLL subgroup with specific clinical features and increased levels of the negative prognostic marker CD49d, the α4-subunit of the integrin VLA-4, which is a key regulator of CLL cell homing to bone marrow (BM). Chemokine-induced inside-out VLA-4 activation, particularly via the CXCL12-CXCR4 axis, increases the arrest of various cell types on VCAM-1 presenting endothelium. Here, we demonstrate that high CD49d expression in tri12 CLL is accompanied by decreased CXCR4 expression. Dissecting functional consequences of these alterations, we observed that tri12 CLL cell homing to murine BM is not affected by CXCR4-CXCL12 blockage using AMD3100 or olaptesed pegol/NOX-A12. In line, CCL21-CCR7 rather than CXCL12-CXCR4 interactions triggered VLA-4-mediated arrests of tri12 CLL cells to VCAM-1 under blood flow conditions. Concordantly, in real-time kinetic analyses we found CCL21 but not CXCL12 being capable to induce inside-out VLA-4 conformational changes in this CLL subgroup. Our results provide novel insights into the peculiar clinico-biological behaviour of tri12 CLL and emphasize its specific chemokine and integrin utilization during pathophysiologically and therapeutically relevant interactions with the microenvironment.


Assuntos
Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Animais , Humanos , Camundongos , Transdução de Sinais
4.
Cancer Res ; 74(23): 6796-805, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25297631

RESUMO

Adoptive T-cell therapy using chimeric antigen receptor-modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2-dependent tumor model, tumor rejection by HER2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNγ receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting.


Assuntos
Interferon gama/imunologia , Interferon gama/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Transferência Adotiva/métodos , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Terapia Baseada em Transplante de Células e Tecidos/métodos , Humanos , Imunoterapia Adotiva/métodos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Interferon/imunologia , Receptores de Interferon/metabolismo , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Células Estromais/imunologia , Células Estromais/metabolismo , Linfócitos T/metabolismo
5.
Cell Rep ; 9(1): 118-128, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25263552

RESUMO

Bone marrow (BM) metastasis remains one of the main causes of death associated with solid tumors as well as multiple myeloma (MM). Targeting the BM niche to prevent or modulate metastasis has not been successful to date. Here, we show that stromal cell-derived factor-1 (SDF-1/CXCL12) is highly expressed in active MM, as well as in BM sites of tumor metastasis and report on the discovery of the high-affinity anti-SDF-1 PEGylated mirror-image l-oligonucleotide (olaptesed-pegol). In vivo confocal imaging showed that SDF-1 levels are increased within MM cell-colonized BM areas. Using in vivo murine and xenograft mouse models, we document that in vivo SDF-1 neutralization within BM niches leads to a microenvironment that is less receptive for MM cells and reduces MM cell homing and growth, thereby inhibiting MM disease progression. Targeting of SDF-1 represents a valid strategy for preventing or disrupting colonization of the BM by MM cells.


Assuntos
Medula Óssea/patologia , Quimiocina CXCL12/antagonistas & inibidores , Mieloma Múltiplo/terapia , Oligonucleotídeos/farmacologia , Animais , Medula Óssea/metabolismo , Neoplasias da Medula Óssea/metabolismo , Neoplasias da Medula Óssea/secundário , Ácidos Borônicos/farmacologia , Bortezomib , Quimiocina CXCL12/biossíntese , Quimiocina CXCL12/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos SCID , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Metástase Neoplásica , Oligonucleotídeos/química , Oligonucleotídeos/genética , Polietilenoglicóis/química , Pirazinas/farmacologia
6.
Blood ; 123(7): 1032-9, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24277076

RESUMO

The CXC chemokine ligand (CXCL12, or stromal cell-derived factor-1 as previously known) plays a critical role for homing and retention of chronic lymphocytic leukemia (CLL) cells in tissues such as the bone marrow (BM). In tissues, stromal cells constitutively secrete and present CXCL12 via cell-surface-bound glycosaminoglycans (GAGs), thereby attracting CLL cells and protecting them from cytotoxic drugs, a mechanism that may account for residual disease after conventional CLL therapy. NOX-A12, an RNA oligonucleotide in L-configuration (Spiegelmer) that binds and neutralizes CXCL12, was developed for interference with CXCL12 in the tumor microenvironment and for cell mobilization. Here, we examined effects of NOX-A12 on CLL cell migration and drug sensitivity. We found that NOX-A12 effectively inhibited CXCL12-induced chemotaxis of CLL cells. In contrast, NOX-A12 increased CLL migration underneath a confluent layer of BM stromal cells (BMSCs) due to interference with the CXCL12 gradient established by BMSCs. In particular, NOX-A12 competes with GAGs such as heparin for CXCL12 binding, leading to the release of CXCL12 from stromal cell-surface-bound GAGs, and thereby to neutralization of the chemokine. Furthermore, NOX-A12 sensitizes CLL cells toward bendamustine and fludarabine in BMSC cocultures. These data demonstrate that NOX-A12 effectively interferes with CLL cell migration and BMSC-mediated drug resistance, and establishes a rationale for clinical development of NOX-A12 in combination with conventional agents in CLL.


Assuntos
Antineoplásicos/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Movimento Celular/efeitos dos fármacos , Quimiocina CXCL12/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/patologia , Células Cultivadas , Quimiocina CXCL12/farmacologia , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Células Jurkat , Linfócitos/efeitos dos fármacos , Linfócitos/fisiologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Proteínas Recombinantes/farmacologia , Migração Transcelular de Célula/efeitos dos fármacos
7.
Neuro Oncol ; 16(1): 21-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24335554

RESUMO

BACKGROUND: Tumor irradiation blocks local angiogenesis, forcing any recurrent tumor to form new vessels from circulating cells. We have previously demonstrated that the post-irradiation recurrence of human glioblastomas in the brains of nude mice can be delayed or prevented by inhibiting circulating blood vessel-forming cells by blocking the interaction of CXCR4 with its ligand stromal cell-derived factor (SDF)-1 (CXCL12). In the present study we test this strategy by directly neutralizing SDF-1 in a clinically relevant model using autochthonous brain tumors in immune competent hosts. METHODS: We used NOX-A12, an l-enantiomeric RNA oligonucleotide that binds and inhibits SDF-1 with high affinity. We tested the effect of this inhibitor on the response to irradiation of brain tumors in rat induced by n-ethyl-N-nitrosourea. RESULTS: Rats treated in utero with N-ethyl-N-nitrosourea began to die of brain tumors from approximately 120 days of age. We delivered a single dose of whole brain irradiation (20 Gy) on day 115 of age, began treatment with NOX-A12 immediately following irradiation, and continued with either 5 or 20 mg/kg for 4 or 8 weeks, doses and times equivalent to well-tolerated human exposures. We found a marked prolongation of rat life span that was dependent on both drug dose and duration of treatment. In addition we treated tumors only when they were visible by MRI and demonstrated complete regression of the tumors that was not achieved by irradiation alone or with the addition of temozolomide. CONCLUSIONS: Inhibition of SDF-1 following tumor irradiation is a powerful way of improving tumor response of glioblastoma multiforme.


Assuntos
Neoplasias Encefálicas/prevenção & controle , Quimiocina CXCL12/antagonistas & inibidores , Recidiva Local de Neoplasia/prevenção & controle , Oligonucleotídeos Antissenso/farmacologia , Terapia por Raios X , Alquilantes/toxicidade , Animais , Neoplasias Encefálicas/induzido quimicamente , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Células Cultivadas , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Etilnitrosoureia/toxicidade , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Humanos , Imageamento por Ressonância Magnética , Camundongos , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/mortalidade , Ratos , Ratos Sprague-Dawley , Receptores CXCR/antagonistas & inibidores , Receptores CXCR/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Taxa de Sobrevida
8.
Proc Natl Acad Sci U S A ; 105(45): 17481-6, 2008 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-18987320

RESUMO

NK cells are promising effectors for tumor adoptive immunotherapy, particularly when considering the targeting of MHC class I low or negative tumors. Yet, NK cells cannot respond to many tumors, which is particularly the case for nonhematopoietic tumors such as carcinomas or melanoma even when these cells lose MHC class I surface expression. Therefore, we targeted primary human NK cells by gene transfer of an activating chimeric receptor specific for HER-2, which is frequently overexpressed on carcinomas. We found that these targeted NK cells were specifically activated upon recognition of all evaluated HER-2 positive tumor cells, including autologous targets, as indicated by high levels of cytokine secretion as well as degranulation. The magnitude of this specific response correlated with the level of HER-2 expression on the tumor cells. Finally, these receptor transduced NK cells, but not their mock transduced counterpart, efficiently eradicated tumor cells in RAG2 knockout mice as visualized by in vivo imaging. Taken together, these results indicate that the expression of this activating receptor overrides inhibitory signals in primary human NK cells and directs them specifically toward HER-2 expressing tumor cells both in vitro and in vivo.


Assuntos
Carcinoma/imunologia , Carcinoma/terapia , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Receptor ErbB-2/imunologia , Animais , Proteínas de Ligação a DNA/genética , Engenharia Genética/métodos , Vetores Genéticos/genética , Humanos , Luciferases , Camundongos , Camundongos Knockout , Receptor ErbB-2/metabolismo
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